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Proietti, Riccardo. "Pulmonary arterial hypertension." Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3425506.
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Strange, Julian William Nevill. "PDE5 inhibition in pulmonary arterial hypertension." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441986.
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Macritchie, Neil Alexander. "Modifying factors in pulmonary arterial hypertension." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/1769/.
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Pulmonary arterial hypertension (PAH) is a debilitating disease of small pulmonary resistance arteries with vasoconstriction and vascular remodelling contributing to the disease pathology. A genetic basis for the disease was linked to heterozygous loss of function mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene. The mutation is found in the majority of familial PAH cases and a significant number of apparently sporadic cases. The low penetrance of the disease in families carrying BMPR2 mutations and the absence of mutations in the majority of idiopathic patients indicates that BMPR2 deficiency alone is insufficient to induce PAH. It is generally accepted PAH has a multi-factorial pathology with endogenous and environmental factors acting in concert with genetic pre-disposition to create the disease phenotype. Enhancement of the serotonin (5-HT) system has been implicated in PAH with the 5-HT transporter (5-HTT) receiving the most attention as a modifying gene in the development of PAH and there is compelling animal and human data implicating a role for increased expression of the 5-HTT as a modulating factor. The aim of this study was to investigate if genetic pre-disposition interacts with other additional modifying factors to create the symptoms of PAH. Transgenic mice overexpressing the 5-HTT (5-HTT+), deficient in BMPR2 (BMPR2+/-) or a double transgenic (5-HTT+/BMPR2+/-) were employed in addition to mice lacking tryptophan hydroxylase 1 (Tph1), the rate limiting enzyme for the synthesis of 5-HT, and therefore lacking peripheral 5-HT (Tph1-/-). Additional known or suspected modifying factors assessed in these genetic models were hypoxia, dexfenfluramine (Dfen) and its major metabolite nordexfenfluramine (NDfen), 5-HT, bone morphogenetic protein-2 (BMP-2), KCNQ channels and the role of gender. Mice were examined in vivo for evidence of a pulmonary hypertensive phenotype following exposure to hypoxia and Dfen. Female 5-HTT+ mice were the only group tohave a rise in two indices of PAH - namely right ventricular pressure (RVP) and vascular remodelling - in room air. Female 5-HTT+ mice also had an exaggerated pulmonary hypertensive phenotype in hypoxia. BMPR2+/- mice, were, unexpectedly least susceptible to hypoxic induced increases in RVP although female mice deficient in BMPR2 (both BMPR2+/- and 5-HTT+/BMPR2+/-) had more extensive vascular remodelling under hypoxia compared with WT and 5-HTT+ mice. Male mice did not express the phenotypic changes just outlined. No synergistic effect was observed between 5-HTT+ and BMPR2+/- that resulted in a more pronounced pulmonary hypertensive phenotype. WT and BMPR2+/- mice were chronically oral-dosed with Dfen. Female mice from both genotypes developed similar degrees of PAH. Male mice did not develop elevated RVP but BMPR2+/- males did have evidence of vascular remodelling, although at a lower level than the females. Female Tph1-/- mice did not develop PAH following Dfen indicating Dfen associated PAH is dependent on peripheral 5-HT synthesis. The presence of intact 5-HT synthesis was also associated with an increased vasoconstrictor response to 5-HT in isolated intralobar pulmonary arteries (IPAs), a situation not paralleled with the other serotonergic vasoconstrictors, Dfen and NDfen, indicating differing mechanisms of action underlying the respective vasoconstrictor responses. The vasoconstrictor action of 5-HT, Dfen, NDfen and the KCNQ potassium channel blocker linopirdine were all assessed in IPAs. Pulmonary arteries from BMPR2+/- mice showed enhanced vasoconstriction to 5-HT and NDfen. 5-HTT+ and 5-HTT+/BMPR2+/- mice showed enhanced vasoconstriction to NDfen but decreased vasoconstriction to 5-HT. Female 5-HTT+/BMPR2+/- mice were the only group tested to show significantly greater vasoconstriction to Dfen compared with WT. The vasoconstrictor response to linopirdine was significantly reduced in BMPR2+/- mice but neither linopirdine nor BMP-2 affected 5- HT induced vasoconstriction. Female gender is an established risk factor for PAH. To investigate possible events that may underlie this risk, male (testosterone) and female (estradiol and 2-methoxyestradiol (2-ME)) sex hormones were assessed for their vasoactive properties in IPAs. All three hormones relaxed pre-constricted vessels but only at supraphysiological (>0.1 µM) concentrations. Each hormone also reduced the vasoconstriction exerted by 5-HT at 10-5 M in male mice but not in females. No such effect, however, was observed in either gender at a physiological (10-9 M) concentration. NDfen induced vasoconstriction was also unaffected by 10-9 M estradiol. Finally, male and female mouse lungs were assessed for protein expression of 5-HT and BMPR2 signalling compounds (p-Smad1/5/8, p-ERK1/2 and p-p38 MAPK). Female mouse lungs displayed higher expression of the mitogenic mediator p-ERK1/2 than male mouse lungs with the other proteins unchanged. In conclusion, this study confirms overexpression of the 5-HTT as a trigger for elevated RVP and vascular remodelling in mice and a cause of more severe hypoxic PAH. BMPR2+/- mice are phenotypically normal in room air and show divergent pulmonary effects following hypoxia with loss of BMPR2 seemingly attenuating hypoxic induced increases in RVP but causing a simultaneous worsening of vascular remodelling, this latter effect consistent with the important role BMPR2 has in maintaining vascular integrity. Dfen induced PAH in mice was found to be dependent on peripheral 5-HT synthesis with BMPR2 mutation not acting as a risk factor. Loss of BMPR2 can enhance vasoconstriction to serotonergic agonists and when combined with overexpression of the 5-HTT, leads to a dramatic increase in sensitivity to Dfen induced vasoconstriction. Evidence was also found for altered KCNQ channel function in transgenic animals. Unexpectedly, female gender emerged as the most crucial risk factor for PAH in this thesis.
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Zilmer, Johansen Anne Katrine. "Estrogen metabolism in pulmonary arterial hypertension." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5199/.
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Pulmonary arterial hypertension (PAH) is a devastating and progressive vasculopathy of the pulmonary arteries for which there is no cure. There is an urgent need for more effective therapies. PAH is characterised by elevated pulmonary arterial pressures and obstructive vascular lesions in the distal vasculature by excessive cellular proliferation. As a result, the right ventricle is placed under excessive strain resulting in adaptive hypertrophy which progresses to maladaptive hypertrophy and failure. PAH is more common in women than in men suggesting that estrogens may be integral to disease pathogenesis. Understanding the biological basis for this sex difference would offer a new treatment paradigm in this devastating cardiovascular disease. Here, we challenged the concept that the estrogen metabolic axis is dysregulated in PAH New insights have revealed a potential contribution of the estrogen metabolizing enzyme, cytochrome P450 1B1 (CYP1B1) in the development of PAH. 17β-estradiol (17β-E2) and estrone (E1) are metabolized by the activity of CYP1B1 to the 2-, 4- and 16-hydroxylated estrogens. Here, we defined the role of CYP1B1 in the pathogenesis of PAH. CYP1B1 expression was increased in both experimental (hypoxia and SU5416+hypoxia) and in heritable and idiopathic PAH (HPAH and IPAH, respectively). Both male and female CYP1B1 knockout mice (CYP1B1-/-) were challenged with chronic hypoxia to induce PAH as assessed by right ventricular systolic pressures (RVSP), right ventricular hypertrophy (RVH) and pulmonary vascular remodeling. CYP1B1-/- mice were protected against hypoxia-induced pulmonary hypertension (PH). CYP1B1 inhibition with the highly potent and selective inhibitor 2,3',4,5'-tetramethoxystilbene (TMS; 3 mg/kg/day by intra-peritoneal injection) attenuated the development of hypoxia-induced PH. Only moderate effects were observed with CYP1B1 inhibition in monocrotaline-induced PH, despite improving survival rates. Female mice that over-express the human serotonin transporter gene (SERT+ mice) develop a spontaneous PAH phenotype at 5 months of age which is dependent on circulating levels of 17β-E2. Here, we provide evidence that the estrogen metabolic axis is dysregulated in these mice and this may underlie their PAH phenotype. The estrogen synthesizing enzyme aromatase and CYP1B1 was increased in whole lung homogenates of female SERT+ mice compared to wild-type mice. Despite increased expression of aromatase, 17β-E2 concentrations were unchanged. CYP1B1 inhibition with TMS (1.5mg/kg/day by intra-peritoneal injection) attenuated the PAH phenotype in female SERT+ mice as assessed by RVSP and pulmonary vascular remodeling Other studies have identified that the 16-hydroxylated metabolites of estrogens (17β-E2 and E1) are the only CYP1B1 metabolites to induce cellular proliferation, with the most profound effects observed with 16α-hydroxyestrone (16α-OHE1). In mice exposed to chronic hypoxia, urinary concentrations of 16α-OHE1 were increased. Chronic dosing of 16α-OHE1 in mice (1.5mg/kg/day by intra-peritoneal injection for 28 days) resulted in the development of a PAH phenotype in female mice only. 16α-OHE1 induced cellular proliferation in human pulmonary arterial smooth muscle cells (hPASMCs) and this was inhibited by a scavenger of reactive oxygen species (ROS) and an inhibitor of extracellular regulated kinase 1/2 (ERK 1/2). 4-hydroxylation is the predominant metabolic pathway activated by CYP1B1 activity and we therefore investigated the effects of the 4-hydroxylated metabolite of 17β-E2 in vivo. 4-hydroxyestradiol (4-OHE2) had no effects on PAH parameters in mice (1.5mg/kg/day by intra-peritoneal injection for 28 days). However, serotonin-induced vasoconstriction of the intra-pulmonary arteries was dramatically reduced in arteries harvested from mice dosed with 4-OHE2. More recent studies have identified that 4-hydroxyestrone (4-OHE1) is the predominant CYP1B1 metabolite in the lungs of mice. Interestingly, despite evidence for a pathogenic function of CYP1B1 activity in vivo, 4-OHE1 inhibited cellular proliferation in hPASMCs as assessed by thymidine incorporation whilst no effects were reported on cell viability. We provide evidence for an altered estrogen metabolic axis in PAH, by in part, overexpression of the putatively pathological CYP1B1. Yet, the dynamic estrogen metabolic profile in pulmonary vascular cells remains undetermined. To address this, we developed a high fidelity HPLC method to quantitatively fate map estrogen metabolism in hPASMCs to determine the dynamic regulation of estrogen metabolism in PAH. We provide the first direct evidence that hPASMCs metabolize 17β-E2 and that estrogen metabolism is pathologically altered in PAH. Our metabolic screen revealed a prominent role for 17β-hydroxysteroid dehydrogenase enzymes in hPASMCs by rapid formation of E1 in all groups studied, increasing with time, with the highest activity in male control hPASMCs and the lowest activity in female control hPASMCs. In female control hPASMCs there was no evidence of CYP activity, whilst numerous metabolites were formed in the other groups studied. The formation of the pathogenic 16α-hydroxylated estrogens was only evident in PASMCs from both male and female PAH patients at 24 and 48 hours. Globally, this study introduces a platform to elucidate effects of PAH insults and potential therapies on the estrogen-metabolic profile in pulmonary vascular cells. Overall, we provide eminent evidence that the estrogen metabolic axis is pathologically altered in PAH and is influenced by gender. This provides a strong rationale for the application of estrogen-sensitive therapies in the management of this highly female discriminating disease.
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Harrison, Rachel Elizabeth. "The genetic basis of pulmonary arterial hypertension." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9530.
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Pulmonary arterial hypertension (PAH) can be idiopathic, hereditary, or develop in association with other diseases. Hereditary PAH is inherited as an autosomal dominant trait with reduced penetrance and variable age of onset. Heterozygous mutations in BMPR2, encoding a type II receptor in the TGF-β signalling pathway, underlie the majority of hereditary cases of PAH. PAH can occur as a rare complication of hereditary haemorrhagic telangiectasia (HHT), a vascular dysplasia caused by mutations in ALK-1, encoding a type I TGF-β receptor and ENG, encoding the accessory TGF-β receptor endoglin. BMP signalling plays an important role in cardiac embryogenesis and PAH is a common complication of congenital heart disease. In this thesis clinical and molecular studies have been performed upon a number of subjects, including those presenting with the combination of HHT and pulmonary hypertension, children presenting with PAH in childhood, and a cohort of adults and children presenting with congenital heart defects unselected for the presence of PAH. Novel heterozygous mutations were identified within the gene encoding ALK-1 and cell-based functional analysis was undertaken to characterise the consequences of these molecular defects. Novel single base pair substitutions in BMPR2 were identified in association with cardiac defects of the outflow tract, indicating that disrupted BMPRII signalling may play a role in the pathogenesis of congenital heart disease. Segregation analysis to determine allele-specific penetrance in a single multigenerational kindred demonstrated that penetrance was significantly higher than previous estimates with profound implications for clinical screening and management of families with hereditary PAH. Taken together, these studies provide insight into the molecular genetic basis of PAH, and identify disrupted signalling in the TGF-β cell-signalling pathway as a fundamental primary defect in the pathophysiology of this devastating disorder.
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James, Victoria Helen. "Molecular genetic investigation of pulmonary arterial hypertension." Thesis, University of Leicester, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436594.
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Tonelli, Adriano R. "Treprostinil Iontophoresis In Idiopathic Pulmonary Arterial Hypertension." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1427825349.
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Assaggaf, Hamza M. "Molecular Risk Factors of Pulmonary Arterial Hypertension." FIU Digital Commons, 2017. https://digitalcommons.fiu.edu/etd/3554.
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The overall objective of the research presented in this dissertation was to investigate molecular risk factors of susceptibility to estrogenic chemicals, polychlorinated biphenyls (PCBs), hormone replacement therapy, and oral contraceptives and how that leads to the development of pulmonary arterial hypertension (PAH). Environmental and molecular risk factors for PAH are not clearly understood. This is a major hurdle for the development of new therapy against PAH as well as understanding individual susceptibility to this disease. Gender has been shown to impact the prevalence of PAH. Although controversial, estrogens have been implicated to be a risk factor for PAH. Thus, we hypothesize that women exposed to estrogenic chemicals are at increased risk of developing PAH when endocrine disrupting chemicals interact with unopposed estrogen to worsen pulmonary arterial disease. In support of this hypothesis, we have accomplished the following: Microarray data on PAH were collected and subsequent meta-analysis was conducted using genome-wide association and environment-wide association approaches on published studies as well as GEO and NHANES data. All PCB geometric mean concentrations found higher levels in people at risk of PAH than people not at risk of PAH. The sum of non-dioxin-like PCBs and the sum of dioxin-like PCBs were significantly higher in people at risk of PAH than people not at risk of PAH. Also, different levels of LOD (including PCBs concentration >LOD, > 50th percentile, 50th-75th percentile, and ≥75th percentile) were significantly higher in people at risk of PAH than people not at risk of PAH. We reported that females used estrogen pills and oral contraceptive were associated with risk of PAH. However, females used progestin and estrogen/progestin pills were not at risk of PAH. Molecular risk factor analysis using machine learning approaches revealed that VAMP2, LAMA5, POLR2C, VEGFB, and PRKCH genes are causal genes of PAH pathogenesis. Gene ontology and pathway analysis of PAH showed that genes involved in the apoptosis pathway, p53 pathway, Ras Pathway, T-cell activation, TGF-beta pathway, VEGF pathway, and Wnt pathway appear to be significantly associated with PAH. Documenting the exposure to estrogenic chemicals among the general U.S. population, and identifying agents and molecular risk factors associated with PAH have the potential to fill research gaps and facilitate our understanding of the complex role environmental chemicals play in producing toxicity in the lungs.
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Tolentino, Chelsea D. "Identifying Genetic Modifiers Contributing to Pulmonary Arterial Hypertension." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1377868964.
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Ferreira, Rita Marisa Nogueira. "Preventive and therapeutic strategies for pulmonary arterial hypertension." Doctoral thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22467.
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Doutoramento em BioquímicaA hipertensão arterial pulmonar (HAP) é uma doença grave, caracterizada por remodelação progressiva da vasculatura pulmonar, frequentemente culminando em insuficiência do ventrículo direito (VD) e morte prematura. Apesar do progresso que tem sido feito nos últimos anos em termos de opções de tratamento, a HAP permanece uma doença incurável, com um mau prognóstico e uma elevada taxa de mortalidade. No presente trabalho, pretendeu-se explorar o potencial de diferentes abordagens preventivas e terapêuticas na HAP experimental. Para isso, três estudos experimentais foram realizados a fim de avaliar o impacto do exercício físico (Estudos I e II) ou do fármaco terameprocol (TMP) (Estudo III) na HAP. No Estudo I mostramos que o exercício físico moderado realizado ao longo da vida induziu diferentes adaptações moleculares nos ventrículos esquerdo e direito. Especificamente, o VD de animais treinados apresentou maiores alterações mitocondriais, mostrando um aumento na expressão de MnSOD e SIRT3, sugestivo de uma melhoria da capacidade antioxidante. Para explorar o impacto do exercício físico na HAP, no Estudo II avaliou-se o seu potencial efeito preventivo na insuficiência do VD secundária a HAP, no modelo animal da monocrotalina (MCT) submetido a 4 semanas de exercício físico em tapete rolante antes do desenvolvimento da doença. Os resultados indicam que o pré-condicionamento com exercício físico preveniu a remodelação da artéria pulmonar e a disfunção, hipertrofia e fibrose do VD. A nível molecular, o exercício físico preveniu o aumento do rácio MHC-beta/alfa e modulou a via de sinalização TWEAK/NF-κB. O exercício físico também preveniu o aumento da expressão da atrogina-1 e induziu um aumento da atividade da MMP-2. Com o objetivo de desenvolver novas estratégias farmacológicas para o tratamento da HAP, no Estudo III foi utilizada uma abordagem proteómica baseada em espetrometria de massa para procurar as vias moleculares moduladas pelo TMP em culturas primárias de células musculares lisas da artéria pulmonar isoladas de ratos injetados com MCT. A análise bioinformática dos dados de proteómica destacou a "regulação do tamanho da célula" e "resposta ao stress do retículo endoplasmático", como processos biológicos sobre-expressos pelo TMP, enquanto os processos biológicos "resposta ao TGF-beta" e "transcrição do ADN" foram encontrados sub-expressos. Dos fatores de transcrição modulados pelo TMP, a sub-expressão do HMGB1 parece estar relacionada com o efeito anti-proliferativo deste fármaco. Estas alterações moleculares induzidas pelo tratamento com TMP podem ter contribuído para a redução da remodelação vascular e consequentemente atenuado a disfunção e hipertrofia do VD associadas à HAP induzida pela MCT. Em geral, os nossos resultados sugerem que o pré-condicionamento com exercício físico e o tratamento com TMP podem ter relevância clínica na HAP. A modulação de vias de sinalização associadas à inflamação parece estar relacionada com os efeitos benéficos destas estratégias preventivas e terapêuticas.
Pulmonary arterial hypertension (PAH) is a severe disease, characterized by progressive remodeling of the pulmonary vasculature, usually culminating in right ventricle (RV) failure and premature death. Despite the progress that has been made in the last few years in terms of treatment options, PAH remains an incurable disease, with a poor prognosis and a high mortality rate. In the current work, we intended to explore the potential of different preventive and therapeutic approaches in experimental PAH. To accomplish that, three experimental studies were performed in order to assess the impact of exercise training (Studies I and II) or the drug terameprocol (TMP) (Study III) in PAH. In Study I, we show that lifelong moderate exercise training induced different molecular adaptations in the left and right ventricles. Specifically, the RV of trained animals presented greater mitochondrial changes, showing an increased expression of MnSOD and SIRT3, suggestive of improved antioxidant capacity. To explore the impact of exercise training on PAH, in Study II we evaluated its potential preventive effect on RV failure secondary to PAH, in the monocrotaline (MCT) animal model submitted to a 4-week treadmill exercise training before disease development. Data indicate that exercise preconditioning prevented pulmonary artery remodeling and RV dysfunction, hypertrophy and fibrosis. At a molecular level, exercise training prevented the increase in beta/alpha-MHC ratio and modulated the TWEAK/NF-κB signaling pathway. Exercise training also prevented the increase of atrogin-1 expression and induced an increase in MMP-2 activity. Envisioning the development of novel pharmacological strategies for PAH treatment, in Study III we used a mass spectrometry-based proteomic approach to search for the molecular pathways modulated by TMP in pulmonary artery smooth muscle cell primary cultures isolated from rats injected with MCT. Bioinformatic analysis of proteome data highlighted the “regulation of cell size” and “response to endoplasmic reticulum stress” as biological processes up-regulated by TMP, while the biological processes “response to TGF-beta” and “DNA-templated transcription” were found down-regulated. From the transcription factors modulated by TMP, the down-regulation of HMGB1 seems to be related with the anti-proliferative effect of this drug. These molecular alterations induced by TMP treatment may have contributed to the reduction of the vascular remodeling and consequently attenuated RV dysfunction and hypertrophy associated to MCT-induced PAH. In overall, our results suggest that exercise preconditioning and TMP treatment can be of clinical relevance in PAH. The modulation of inflammation-related signaling pathways seems to be behind the benefits of these preventive and therapeutic strategies.
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Pullamsetti, Soni. "Role of Dimethylarginine Dimethylaminohydrolases (DDAH) in pulmonary arterial hypertension." Giessen VVB Laufersweiler, 2006. http://geb.uni-giessen.de/geb/volltexte/2006/2892/index.html.
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Ling, Yi. "Demographics, epidemiology and prognostic factors in pulmonary arterial hypertension." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5462/.
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Prevalent patients were over-represented in many pulmonary hypertension registries and clinical trials. These patients have better survival compared with incident patients. As pulmonary hypertension (PH) is diagnosed and managed in designated pulmonary hypertension centres only in the United Kingdom (UK) and Ireland, this provides a unique opportunity to define the demographics, epidemiology and outcomes of a large cohort of purely incident, treatment-naive idiopathic, heritable and anorexigen-associated pulmonary arterial hypertension (PAH) patients. We included all newly diagnosed, treatment naive patients diagnosed in all eight PH centres in the UK and Ireland between January 2001 and December 2009 in our study. We used the same inclusion criteria used in the French and Scottish registries to define our idiopathic, heritable and anorexigen-associated PAH patients. We further refined our criteria for idiopathic, heritable and anorexigen-associated PAH by excluding patients with evidence of parenchymal lung disease on thoracic CT. These excluded patients (refer as Pre-capillary pulmonary hypertension co-existing lung disease in this thesis) were managed as idiopathic PAH by their PH physicians and otherwise satisfied the usual haemodynamic and pulmonary function criteria used to define idiopathic PAH in many PH registries and clinical trials. We divided our idiopathic, heritable and anorexigen-associated PAH patients into two age subgroups according to their median age to study the effect of age on their phenotypes and survival. We also divided our idiopathic, heritable and anorexigen-associated PAH patients into three subgroups according to their year of diagnosis to study the changing epidemiology of the disease over the past decade. We also compared the baseline characteristics and outcomes of our idiopathic, heritable and anorexigen-associated PAH patients with PAH with ‘co-existing lung disease’ patients. Firstly, we confirmed that the demographics, epidemiology and survival of incident idiopathic, heritable and anorexigen-associated PAH has changed compared with patients from the pre-disease targeted therapy era of the 1980s, and continued to evolve in the UK and Ireland over the past decade. The incidence of idiopathic PAH continued to increase over the past decade in the UK and Ireland, most likely reflecting increased referral to the pulmonary hypertension centres. Patients were still referred late with severe functional and haemodynamic impairment. Greater education is needed to raise awareness amongst the non-pulmonary hypertension community of the changing epidemiology of the disease. We have used our incident study cohort of idiopathic, heritable and anorexigen-associated PAH to validate currently available survival prediction models in PAH. Our results suggested that some survival prediction models performed better than others. We observed different phenotypic characteristics and survival between younger and older idiopathic, heritable and anorexigen-associated PAH patients. Baseline variables with prognostic significance were also different between younger and older idiopathic, heritable and anorexigen-associated PAH patients. Interestingly, obesity was associated with better survival in older patients but the contrary in younger patients. We also explored the prognostic significance of short term improvement in six minute walk distance and functional class in response to treatment in incident idiopathic, heritable and anorexigen-associated PAH. Change in six minute walk distance after three months of pulmonary hypertension treatment was associated with improved survival in patients with low baseline six minute walk distance. Change in functional class at six months was also predictive of survival in our idiopathic, heritable and anorexigen-associated PAH patients. Finally, we observed that pre-capillary pulmonary hypertension with co-existing lung disease patients who otherwise satisfied the usual haemodynamic and pulmonary function criteria for idiopathic PAH had significantly different demographics and worse survival compared with idiopathic PAH patients. Better characterisation of this subgroup of PH patients will avoid bias from inclusion of these patients as idiopathic PAH in future clinical trials.
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Ribeiro, Diana Raquel Santos. "The role of urocortin-2 in pulmonary arterial hypertension." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/15381.
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Mestrado em Biologia Molecular e CelularPulmonary arterial hypertension (PAH) is a syndrome based on diverse aetiologies, characterized by a persistent increase in pulmonary vascular resistance and overload of the right ventricle (RV), leading to heart failure (HF) and death. Urocortin (UCN)-2 is a peptide highly expressed in the cardiovascular system that has shown promising therapeutic effects in several studies both in humans and animal models of HF. Thus, this study aims to explore the effects of UCN-2 treatment in an animal model of RV HF secondary to PAH and its impact on myocardial function. Male Wistar rats (180-200g) randomly received monocrotaline (MCT, 60mg/kg) or vehicle. After 14 days, animals were randomly assigned to receive UCN-2 treatment (5μg/kg/day) or vehicle. The study resulted in 4 groups: CTRL (n=9), CTRL+UCN-2 (n=9), MCT (n=7) and MCT+UCN-2 (n=10). Echocardiographic, hemodynamic studies and sample collection were performed 24-25 days after MCT administration. Only significant results (mean±SEM, p<0.05) are given. MCT animals developed PAH, demonstrated by impaired pulmonary flow, RV dilation and increased RV pressures, as well as decreased cardiac output. MCT administration also resulted in RV hypertrophy. UCN-2 treatment was able to restore PAH-induced severe abnormalities in cardiac function and structure. Moreover, Kaplan-Meier analysis showed increased survival rate for MCT+UCN-2 rats when compared with the MCT group. The molecular studies revealed an altered genetic expression of the UCN-2/CRHR2 system components in the MCT animals, as shown by the increase in molecular markers of hypertrophy, overload, hypoxia and apoptosis that were reversed with UCN-2 treatment. As well as an impaired protein activation/phosphorylation seen in peptides pertaining to different signaling pathways. In conclusion, we show that UCN-2 chronic treatment is able to restore PAHinduced severe abnormalities in cardiac function and structure, as well as to reverse the changes in the expression of markers of cardiac overload, hypertrophy, hypoxia and apoptosis induced by the disease. The beneficial effects of UCN-2 seem to be associated with the modulation of numerous signaling pathways, such as survival and proliferation. These findings suggest that the UCN-2/CRHR2 pathway has a relevant role on the pathophysiology of PAH and progression to RV failure, representing a potential therapeutic target.
A hipertensão arterial pulmonar (HAP) é uma síndrome caracterizada por um aumento progressivo das resistências vasculares pulmonares e sobrecarga sobre o ventrículo direito que potencialmente levam à insuficiência cardíaca (IC) direita e consequentemente à morte. A urocortina (UCN)-2 é um péptido altamente expresso a nível cardiovascular que tem exibido efeitos terapêuticos benéficos tanto em humanos como em modelos animais de IC. Este estudo tem como principal objetivo explorar os efeitos da UCN-2 num modelo animal de IC ventricular direita (VD), secundário à HAP, e o seu impacto na função miocárdica. Ratos Wistar machos receberam aleatoriamente uma injeção de monocrotalina (MCT) ou veículo. Após 14 dias, os animais foram novamente sorteados para receber tratamento com UCN-2 ou veículo. Do estudo resultaram 4 grupos experimentais: CTRL, CTRL+UCN-2, MCT e MCT+UCN-2. As avaliações ecocardiográficas, estudos hemodinâmicos e colheita de amostras para análise morfométrica, histológica e molecular foram realizados 24-25 dias após a administração de MCT. Os animais injetados com MCT desenvolveram HAP e IC VD, demonstrado pelo comprometimento do fluxo pulmonar, dilatação VD e aumento das pressões VD, assim como um débito cardíaco diminuído. A administração de MCT também levou à hipertrofia VD. O tratamento com UCN-2 conseguiu recuperar as alterações induzidas pela HAP na função e estrutura cardíacas. Ainda, os animais MCT+UCN-2 tiveram uma maior taxa de sobrevivência quando comparados com os MCT. Os estudos moleculares revelaram uma expressão genética e uma fosforilação proteica alterada nos animais MCT, de alguns componentes do sistema UCN-2/CRHR2. Em suma, com este estudo demonstramos que o tratamento crónico com UCN-2 é capaz de restaurar as alterações induzidas pela HAP na função e estrutura cardíacas, assim como reverter as alterações na expressão de marcadores cardíacos de sobrecarga, hipertrofia, hipóxia e apoptose induzidos pela doença. Estes resultados sugerem que a via UCN-2/CRHR2 tem um papel relevante na fisiopatologia da HAP e progressão para IC, representando um potencial alvo terapêutico.
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Arshad, Haroon. "Mathematical modelling of pulmonary arterial smooth muscle cell subtypes." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/mathematical-modelling-of-pulmonaryarterial-smooth-muscle-cell-subtypes(c1110807-d94d-487c-90b8-8714d5e42d16).html.
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Alteration in the tone of pulmonary arteries may lead to disease such as pulmonary hypertension often associated with major cardiac complications. This dysfunction is partly in the pulmonary arterial smooth muscle cells (PASMCs) where the excitation-contraction coupling is modified by ion channel behaviour to increase the contractile force. Mathematical models of systemic smooth muscle cells (SMCs) that incorporate electrophysiological and chemomechanical mechanisms to understand the underlying cellular physiology have been successfully employed. Models of pulmonary arterial smooth muscle cells (PASMCs) are only beginning to emerge. Mathematical model prototyping with available experimental data and model investigation from different parameter values is a time-consuming and complex process. This thesis is concerned with the development and validation of mathematical models of excitation-contraction coupling in three types of PASMCs of the rat species, one homogeneous type originating from the distal pulmonary arteries and two from proximal pulmonary arteries. Some key novel additions from previous vascular SMC models include the distinct modelling of Ca2+ in the subplasmalemmal cytosolic region, incorporation of subunit-specific currents from the K+ channel family and a generic G-protein receptor model able to reproduce complex Ca2+ profiles. The main pulmonary and systemic arteries statistically differ in its response to phenylephrine in a wire myograph. The ionic currents of the models were validated against experimental data largely from rat species. The models replicate the recordings of Ca2+ and the resting potential (Em) profiles arising from agonist-induced cytosolic Ca2+ ([Ca2+]i) stimulation (G-protein activation), nifedipine, ryanodine, caffeine and niflumic acid. The distal PASMC model was sensitive to an increase in [Ca2+]i from G-protein activation although were less likely to reproduce Ca2+ oscillations than proximal PASMCs. The proximal models determined the likely proximal PASMC type in literature experiments recording [Ca2+]i and Em. I have developed software that enables other users to simulate Ca2+ and Em changes in SMC studies and the ability to parse a master file describing the mathematical model into different language formats to increase productivity. These models provide a foundation for further studies to better understand PASMC function in the context of normal physiology as well as pathological conditions.
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Rhodes, Christopher James. "Iron metabolism and biomarkers in idiopathic pulmonary arterial hypertension." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/6915.
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Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterised by increased vascular resistance and remodelling of the pulmonary vasculature. This causes strain on the right ventricle, leading eventually to failure and death. Iron status is thought to influence pulmonary vascular tone, particularly in hypoxia, and may be important in IPAH. Proteomic studies of lung tissues from IPAH patients versus control lobectomy samples revealed downregulated levels of the haemoglobin- and haem-scavenging proteins haptoglobin (Hp) and haemopexin. Plasma levels of Hp were also reduced in IPAH and related to the Hp genotype. Consistently low Hp levels were associated with dysregulated iron homeostasis in IPAH patients. Iron deficiency, as defined by raised plasma soluble transferrin receptor (sTfR) levels, was prevalent in IPAH patients and related to increased levels of the master iron regulator hepcidin. Iron deficiency was also associated with poor exercise capacity, disease progression and mortality. Circulating sTfR levels were compared against other iron-related and established prognostic biomarkers in IPAH, including N-terminal brain natriuretic peptide (NT-proBNP), red cell distribution width (RDW), growth differentiation factor-15 and interleukin-6. All predicted survival and related to disease severity in IPAH, but RDW and NT-proBNP provided the most information when clinical and haemodynamic indices were considered. Dysfunctional bone morphogenetic protein (BMP) receptor type II (BMPR2) signalling contributes to idiopathic as well as heritable PAH. Downregulation of BMPR2, but not the other type II BMP receptors ActRIIA and ActRIIB, led to increased hepcidin expression and secretion in response to BMP-6 stimulation in hepatocellular carcinoma HepG2 cells. Hepcidin expression was also enhanced in rat lung tissue following 1 or 2 weeks exposure to hypoxia. In conclusion, dysregulation of iron homeostasis is common in IPAH and appears to be important clinically. Increased hepcidin levels may contribute to this phenomenon and reflect the dysfunctional BMPR2 signalling associated with the disease.
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Suen, Colin. "Novel Therapeutic Strategies for the Treatment of Pulmonary Arterial Hypertension." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/36242.
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Pulmonary arterial hypertension (PAH) is a progressive disease that results in increased pulmonary vasculature resistance, causing right ventricular (RV) remodeling, which eventually progresses into right heart failure and mortality. New and emerging therapeutic strategies involve regenerative approaches to repair the underlying vascular pathology using regenerative cell therapy and methods to alleviate RV dysfunction in the setting of fixed RV afterload. In the first section of the thesis, we investigated the role of EPC paracrine mechanisms in the treatment of PAH. We characterized the paracrine function of EPCs by demonstrating that EPC conditioned medium enhances endothelial cell migration, survival and angiogenesis in vitro. We further examined the role of secreted extracellular vesicles in the paracrine function of EPCs, which played a minor role in promoting wound healing. However, using the monocrotaline rat model of PAH, we did not demonstrate a consistent benefit on RV pressures or remodeling with EPCs or EPC conditioned medium. The lack of effect may be related to the advanced phenotype observed in our model of PAH.
Survival in severe pulmonary arterial hypertension (PAH) is related to the ability of the right ventricle (RV) to adapt to increased afterload. Therefore, we explored the effect of genetic background on right ventricular adaptation and survival in a rat model of severe (PAH). Compared to the conventional Sprague-Dawley rat strain, we observed high mortality in the Fischer SUHx model of severe PAH. This was related to a strain-dependent failure of RV adaptation, as evidenced by RV dilatation, RV contractile dysfunction, decreased cardiac ouptut and decreased exercise capacity. Further analysis by gene expression microarrays and fluorescence microangiography demonstrate that failure of RV adaptation is due at least in part due to lack of adequate microvascular angiogenesis in the hypertrophied RV. This work lays the foundation for the section on RV-specific therapy that follows.
Using the Fischer model of maladaptive RV remodeling, we tested whether cardiotrophin-1 (CT-1), a pro-angiogenic and cardioprotective cytokine, could improve RV adaptation. We demonstrated that as a rescue treatment, CT-1 reduced RV dilatation and function without influencing RV afterload, which suggests improved RV adaptation. These changes were associated with an increase in RV capillary density. As an early-stage preventative treatment, in addition to improving RV remodeling, CT-1 also reduced pulmonary pressures. These hemodynamic changes suggest that CT-1 may also have a direct impact on vascular tone or the underlying pulmonary vascular pathology.
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Murray, Alicia. "Interactions between potassium channels and serotonin in pulmonary arterial hypertension." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/563/.
Full textAbstract:
Pulmonary arterial hypertension (PAH) is a progressive disease which results from increases in mean pulmonary artery pressure and pulmonary vascular resistance. If untreated it leads to right ventricular failure and death. 5-Hydroxytryptamine (5-HT) has been implicated in the disease process and is thought to promote both vasoconstriction and remodelling of the pulmonary vasculature. The activity of potassium ion (K+) channels plays a major role in influencing pulmonary artery tone by regulating resting membrane potential, intracellular Ca2+ concentration and contraction of vascular smooth muscle. This study aimed to investigate possible interactions between 5-HT and K+ channels in the development of PAH in the mouse. The actions of 5-HT and a range of K+ channel blockers were investigated on isolated intralobar pulmonary arteries (IPA) from wild type (WT) mice and mice over-expressing the serotonin transporter (5HTT), which spontaneously develop PAH. Both 5-HT and linopirdine, a KCNQ K+ channel inhibitor, were found to induce contraction of IPA, but were more potent in IPA from WT mice than 5-HTT+ mice. The 5-HT induced vasoconstriction was found to involve influx of Ca2+ from the extracellular space, Ca2+ release from the sacroplasmic reticulum and a rho kinase–dependent increase in the sensitivity of the contractile machinery of pulmonary artery smooth muscle cells (PASMC) to intracellular Ca2+. Ca2+ entered the cell via both voltage operated calcium channels (VOCC), activated by membrane depolarisation, and a separate Ca2+ entry pathway, the latter appearing to contribute more in 5-HTT+ mice. The effects of linopirdine were shown to be due entirely to the entry of Ca2+ through VOCC in both WT and 5-HTT+ mice IPA. The difference in vasoconstrictor potency between WT and 5HTT+ mice was not seen with any other K+ channel blocker, suggesting a selective loss of KCNQ channels and/or VOCC in PAH resulting from 5HTT over expression. KCNQ channel activity was further investigated using the KCNQ channel openers, flupirtine and retigabine. These agents were more potent in dilating IPA from WT mice compared to 5-HTT+ mice, consistent with the loss of expression or activity of KCNQ channels in 5-HTT+ mice. Despite this, orally administered flupirtine was shown to reverse two indices of established PAH in the 5HTT+ mice; right ventricular pressure and right ventricular hypertrophy. This action of flupirtine was also seen in chronic hypoxic mice, where it prevented the development of PAH. In conclusion, this study provides evidence of an interaction between KCNQ channels and the 5-HT system in the development of PAH. By showing that a KCNQ channel opener can attenuate PAH, both in the developing and established disease situation, this study proposes a new potential therapeutic target in the treatment of PAH.
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Martin, Robert Brian. "Development and Resolution of Pulmonary Arterial Hypertension in RAO Horses." Thesis, Virginia Tech, 2003. http://hdl.handle.net/10919/9613.
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Equine recurrent airway obstruction (RAO) is associated with airway inflammation and bronchoconstriction in clinically affected horses. Horses demonstrating severe pulmonary compromise develop concurrent secondary pulmonary hypertension. The development of pulmonary hypertension is well documented in RAO affected horses, however, it is not known how rapidly increases in pulmonary artery pressure occur after the onset of RAO. It is also not known if pulmonary hypertension resolves concurrently with resolution of RAO. The goal of this study was to measure pulmonary artery pressure in RAO affected horses during the development and resolution of RAO. To accomplish this, three RAO affected and three normal horses were placed in a challenge environment where clinical parameters, pulmonary function, right heart and pulmonary artery pressures were measured on day 1, 3 and 5. After evaluating horses on day five, their environment was modified to reduce exposure to respirable debris and anti-inflammatory medication (dexamethasone) was initiated. Identical clinical parameters were measured on days 7 and 9. In our study, the arterial oxygen content in RAO horses was significantly less that that of control horses from day 1 through day 9. A concurrent increase in pulmonary artery pressure also developed on day 3 in RAO affected horses, and persisted through day 5. While some trend towards a difference between groups was noted, no other significant differences were observed between RAO and normal horses. These findings suggest that horses with severe RAO also develop significant increase in pulmonary artery pressure, which rapidly resolves with appropriate management of RAO.Master of Science
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Chen, Chien-Nien. "Pharmacological effect of histone deacetylase inhibitors on pulmonary arterial hypertension." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/17770.
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Pulmonary hypertension (PH) is characterized by structural remodelling of pulmonary arteries and arterioles, the result, at least in part, of excessive cell proliferation, resistance to cell death and hyperactive inflammatory reactions. Currently available treatments targeting the hyper-proliferative and pro-inflammatory pathology are limited. Epigenetic programming, dynamically regulated by histone acetylation, is an important mechanism for cell proliferation and survival. Aberrant changes of histone acetylation, modulated by histone deacetylase (HDAC), are shown in many proliferative and inflammatory disorders, especially cancer, and may contribute to the phenotypical changes in remodelling and overall to the development of PH. Hypothetically, HDAC inhibitors have therapeutic potential by reversing the imbalance of acetylation. I examined the correlations between HDAC expression and PH development, followed by evaluation of the pharmacological effects and possible mechanisms of two HDAC inhibitors, class I inhibitor valproic acid (VPA) and pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), on animal models and cellular systems. Altered HDAC expression, specifically increased HDAC1 and HDAC5 along with elevation of anti-apoptotic marker Bcl-2, were found in lungs from patients with idiopathic pulmonary arterial hypertension and chronically hypoxic rats. In in vivo studies, VPA and SAHA ameliorated the established PH in both hypoxia- and monocrotalineinduced PH rat models, by reducing pulmonary arterial pressure, right ventricular hypertrophy and pulmonary vascular muscularization, in parallel with increasing histone acetylation. In in vitro studies, VPA and SAHA inhibited stimulated cell growth of pulmonary artery smooth muscle cells and cytokine release from endothelial cells. Biochemical analysis indicated these two inhibitors exert anti-proliferative effects comprising cell cycle arrest by upregulation of p21 and apoptotic induction by downregulation of Bcl-2. Collectively, this study shows the contribution of abnormal HDAC activity to vascular pathology of PH and provides a preclinical basis to further explore the therapeutic potential of HDAC inhibitors in human PH.
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Fowler, Robin. "The impact of elevated pulmonary artery pressure on exercise responses." Thesis, Curtin University, 2012. http://hdl.handle.net/20.500.11937/2637.
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Background and research questions. The four studies reported in this thesis investigated the implications of an elevated pulmonary artery pressure (PAP) on the response to an exertional challenge. The level of symptoms and exertion that healthcare professionals consider appropriate for patients with pulmonary arterial hypertension (PAH) was explored in the first study. In studies two, three, and four, exercise responses and exercise testing were evaluated in individuals with an elevated PAP on exercise, but a normal PAP at rest (exercise-induced pulmonary arterial hypertension, [EIPAH]).The following research questions were addressed: 1. Is there consistency in the advice given by healthcare professionals in Australia regarding physical exertion and symptoms, and in referral for exercise rehabilitation, for patients with PAH? 2. What are the clinical implications of an elevated PAP in symptomatic individuals with risk factors for PAH but who have a normal PAP at rest (EIPAH)? 3. Can the six-minute walk test (6MWT) identify reduced exercise capacity and accurately estimate aerobic capacity in individuals with EIPAH? 4. Are the haemodynamic and symptomatic responses to maximal and submaximal resistance exercise similar to the responses demonstrated during comparable intensities of aerobic exercise in individuals with EIPAH?Abstracts for the reported studies. This PhD program formed the basis for four publications in peer reviewed, international, scientific journals. These four publications are summarised, in abstract form, below. The full manuscripts of these publications constitute Chapters 4-7 of this thesis.
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Hollander, Ellen Herdis. "Wave-intensity analysis of pulmonary arterial blood flow in anesthetized dogs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ31035.pdf.
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Game, Alexander B. "Effect of a hockey season on pulmonary function and arterial desaturation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0015/MQ47033.pdf.
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Hogg, Dayle S. "Cationic currents in pulmonary arterial cells and their sensitivity to hypoxia." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393392.
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Gurung, R. "Novel biomarkers in vascular remodelling and inflammation in pulmonary arterial hypertension." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1508496/.
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Pulmonary arterial hypertension (PAH) is a progressive and fatal disease driven by vascular remodelling and inflammation. Presenting symptoms of PAH are nonspecific, making diagnosis often late when the disease is irreversible. Endothelial damage occurs early in the disease progress and medial thickening due to proliferating smooth muscle cells in the distal arteries is the earliest known pathology. Circulating microparticles (MPs) are vesicles released by various cells and used as markers of cell activation during inflammation and vascular damage in various vasculopathies. Thus, the aim was to identify circulating MPs, with a special interest to smooth muscle MPs, to be used as biomarkers in PAH. Initially, I characterised smooth muscle MPs derived from growing smooth muscle cells in culture. Smooth muscle MPs were positive for platelet derived growth factor receptor- β (PDGFR-β ), endoglin, intracellular cell adhesion molecule (ICAM-1) and neural glial antigen 2 (NG2) but negative for platelet endtholial cell adhesion molecule-1 (PECAM-1). High levels of endoglin+/ICAM-1+ and low levels of PDGFRβ +/NG2+ MPs were derived from human umbilical cord vein endothelial cells. PDGF, tumour necrosis factor-α, transforming growth factor β, and endothelin-1 were growth factors and cytokines that could stimulate the release of MPs from growing smooth muscle cells. Having characterised smooth muscle MPs (SMMPs), I investigated their levels in plasma from pulmonary arterial hypertension patients and compared them with other vascular inflammatory diseases. Circulating levels of total, smooth muscle, endothelial, leukocyte, and platelet MPs were elevated in PAH patients compared to age-matched healthy controls and in patients with myocardial ischemia and HIV. PAH drugs, particularly prostacyclin mimetics were effective in decreasing MP numbers in cell culture and in patients after long-term therapy. The function of MPs and mechanism of their release inhibition by the prostacyclin analogue treprostinil was investigated. MPs in plasma and cultured smooth muscle cells were procoagulant, as measured using a thrombin generation assay, and induced smooth muscle proliferation. Treprostinil inhibited SMMP release via the prostacyclin receptor and the prostaglandin E2 receptor, and also inhibited cell proliferation. Furthermore, the mimetic inhibited calcineurin/nuclear factor of activated T-cells (NFAT) signalling, which was partially reversed by blockade of peroxisome proliferator activated receptor. As calcineurin/NFAT is a driver of smooth muscle proliferation and remodelling, it may be a novel target through which prostacyclin may be signalling.
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George, Peter Michael. "The role of interferon in the development of pulmonary arterial hypertension." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/26116.
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Interferons (IFNs) are an integral part of the innate immune response to viral infection. As well as possessing important anti-viral properties, they possess immunomodulatory, cytotoxic and anti-tumoural functions. As a consequence, the IFNs (mainly type I IFN) have been utilised for the treatment of human disease where they represent important therapies, most commonly in the treatment of chronic hepatitis C virus (HCV). However, there is now emerging evidence of an association between type I IFN drug treatment and the development of severe and at times irreversible pulmonary arterial hypertension (PAH). Through the course of this PhD I have investigated potential mechanisms for type I IFN induced PAH and have identified the IFN regulated protein IP10 and the promitogen and vasoconstrictor endothelin (ET)-1 as important candidate mediators. It is well established that autoimmune conditions such as systemic sclerosis, where PAH is a common complication, are typified by chronic activation of type I IFN pathways. I have used the observation that IFN drug treatment may cause PAH, as a platform to hypothesise that endogenous type I IFN production may be important in the pathogenesis of systemic sclerosis associated PAH. Through a comprehensive approach utilising in vitro cell culture models, in vivo animal models of disease and patient samples, I have demonstrated that endogenously produced type I IFN plays an important role in the development of systemic sclerosis associated PAH and also idiopathic PAH. I have also gone on to show that other facets of the immune system appear to have pathogenic relevance in this devastating and still under-characterised disease. I conclude that a dysregulated and chronically active innate immune system plays a pathological role in the development of pulmonary arterial hypertension.
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Hurst, Liam Andrew. "The role of tumour necrosis factor alpha in pulmonary arterial hypertension." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648471.
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Hood, Katie Yates. "Vasoactive factors, Nox isoforms and redox biology in pulmonary arterial hypertension." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7973/.
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Pulmonary arterial hypertension (PAH) is characterised by elevated pulmonary arterial pressures and obstructive lesions in the distal vasculature. As a result, the right ventricle is placed under excessive strain resulting in adaptive hypertrophy, progressing to maladaptive hypertrophy and failure. Women develop PAH more frequently than men. It is postulated that 17β-estradiol (E2) plays a role in disease pathogenesis and/or the E2 metabolic axis may be dysregulated in PAH. Growing evidence also implicates a role for ROS and oxidative stress in PAH, yet mechanisms linking these systems are elusive. We hypothesised that either E2 or the E2 metabolite, 16α-hydroxyestrone (16αOHE1), stimulates Nox-induced ROS generation and proliferative responses in human pulmonary artery smooth muscle cells (hPASMC) and that, in PAH, aberrant growth signaling promotes vascular remodeling. The pathophysiological significance of E2-Nox-dependent processes was studied in female Nox1-/- and Nox4-/- mice exposed to chronic hypoxia. HPASMCs from female non-PAH individuals (control hPASMC) and female PAH patients (PAH-hPASMC) were exposed to E2 and 16αOHE1 in the presence/absence of inhibitors of Nox1, Nox2 and Nox4, cytochrome P450 1B1 (CYP1B1) and estrogen receptors (ER), ERα, ERβ and G-protein coupled estrogen receptor (GPER). E2, through ERβ, increased Nox1 and Nox4-derived O2- and redox-sensitive growth in control hPASMCs. 16αOHE1, through ERα activation, stimulated O2- production in control hPASMCs and PAH-hPASMCs. E2- -stimulated O2- production was inhibited by CYP1B1 blockade. Basal expression of Nox1 and Nox4 was potentiated in PAH-hPASMCs. In control hPASMCs, 16αOHE1 increased p47phox and poldip2 and Nox1 expression. In PAH-hPASMCs, 16αOHE1 decreased nuclear factor erythroid-2-related factor-2 (Nrf-2) activity and expression of Nrf-2-regulated antioxidant genes in PAH-hPASMCs. Female Nox1-/-, but not Nox4-/- mice were protected against chronic hypoxia-induced pulmonary hypertension and vascular remodeling. Expression of CYP1B1 was increased in pulmonary arteries of wild-type and Nox4-/- mice exposed to hypoxia, yet this induction in CYP1B1 expression was absent in those arteries from hypoxic Nox1-/- mice. Findings detailed in Chapter 3 show that in PAH-hPASMCs, 16αOHE1 stimulates redox-sensitive cell growth through both Nox1 and Nox4. In vivo studies exhibited protection against pulmonary hypertension specifically in Nox1-/- mice. This study provides new insights through Nox1/ROS and Nrf-2 whereby 16αOHE1 influences hPASMC function, which when upregulated may contribute to vascular injury in PAH.
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Mohamed, Nura. "Assessment of nanomedicine preparations as potential therapies for pulmonary arterial hypertension." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/45651.
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Pulmonary arterial hypertension (PAH) is an aggressive disease with poor prognosis, no available cure and with survival rates of 2-5 years after diagnosis. However, there are drugs available, which work by enhancing dilator pathways or blocking constrictors that limit progression of the disease; Unfortunately these drugs have the critical limitation of dilator effects in the systemic circulation and are associated with class specific side effects. One way of overcoming systemic (and other) side effects is to employ a nanomedicine approach where drugs can be encapsulated in a nano-sized (≈100nm) carrier molecule and directed specially to the diseased vessels of the lung. Nanoparticles used in the medical field are classified to being organic or inorganic. In my PhD I investigated the effects of two nanomedicine formulations in biological systems one organic and one inorganic. Firstly I prepared an iron (Fe) containing metal organic framework (MOF), MIL-89 and it is PEGylated form (MIL-89 PEG). MIL-89 preparations confirmed to the predicted structure and were non-toxic in vitro and in vivo with some potential anti-inflammatory effects at high concentrations. Unfortunately loading MIL-89 with drug and assessing effects in relevant systems was beyond the scope of my PhD thesis, but future development of MIL-89 in a PAH setting is discussed throughout. Secondly I studied the chemical and biological effects of a novel NO-releasing nanomedicine formulation consisting of nitrated polymers (NO-NP). NO-NP released NO, is relatively non-toxic, inhibited some aspects of inflammation and was an effective vasodilator with selectively towards pulmonary artery over systemic vessels (aorta). The data in my thesis are consistent with the idea that a nanomedicine approach is achievable in PAH and my personal view is that in the future PAH drugs will be delivered as targeted therapies with the potential of converting PAH into a chronic drug-managed condition.
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Hansmann, Georg [Verfasser]. "The Protective Role of PPARgamma in Pulmonary Arterial Hypertension / Georg Hansmann." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2010. http://d-nb.info/1024007235/34.
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Cantoni, Silvia <1974>. "Development of strategies for vascular damage repair in Pulmonary Arterial Hypertension." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5799/1/Cantoni_Silvia_tesi.pdf.
Full textAbstract:
Pulmonary arterial hypertension (PAH) is a progressive and rare disease with so far unclear pathogenesis, limited treatment options and poor prognosis. Unbalance of proliferation and migration in pulmonary arterial smooth muscle cells (PASMCs) is an important hallmark of PAH.
In this research Sodium butyrate (BU) has been evaluated in vitro and in vivo models of PAH. This histone deacetylase inhibitor (HDACi) counteracted platelet-derived growth factor (PDGF)-induced ki67 expression in PASMCs, and arrested cell cycle mainly at G0/G1 phases. Furthermore, BU reduced the transcription of PDGFRbeta, and that of Ednra and Ednrb, two major receptors in PAH progression. Wound healing and pulmonary artery ring assays indicated that BU inhibited PDGF-induced PASMC migration. BU strongly inhibited PDGF-induced Akt phosphorylation, an effect reversed by the phosphatase inhibitor calyculinA.
In vivo, BU showed efficacy in monocrotaline-induced PAH in rats. Indeed, the HDACi reduced both thickness of distal pulmonary arteries and right ventricular hypertrophy.
Besides these studies, Serial Analysis of Gene Expression (SAGE) has be used to obtain complete transcriptional profiles of peripheral blood mononuclear cells (PBMCs) isolated from PAH and Healthy subjects. SAGE allows quantitative analysis of thousands transcripts, relying on the principle that a short oligonucleotide (tag) can uniquely identify mRNA transcripts. Tag frequency reflects transcript abundance. We enrolled patients naïve for a specific PAH therapy (4 IPAH non-responder, 3 IPAH responder, 6 HeritablePAH), and 8 healthy subjects. Comparative analysis revealed that significant differential expression was only restricted to a hundred of down- or up-regulated genes. Interestingly, these genes can be clustered into functional networks, sharing a number of crucial features in cellular homeostasis and signaling. SAGE can provide affordable analysis of genes amenable for molecular dissection of PAH using PBMCs as a sentinel, surrogate tissue.
Altogether, these findings may disclose novel perspectives in the use of HDACi in PAH and potential biomarkers.
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Cantoni, Silvia <1974>. "Development of strategies for vascular damage repair in Pulmonary Arterial Hypertension." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5799/.
Full textAbstract:
Pulmonary arterial hypertension (PAH) is a progressive and rare disease with so far unclear pathogenesis, limited treatment options and poor prognosis. Unbalance of proliferation and migration in pulmonary arterial smooth muscle cells (PASMCs) is an important hallmark of PAH.
In this research Sodium butyrate (BU) has been evaluated in vitro and in vivo models of PAH. This histone deacetylase inhibitor (HDACi) counteracted platelet-derived growth factor (PDGF)-induced ki67 expression in PASMCs, and arrested cell cycle mainly at G0/G1 phases. Furthermore, BU reduced the transcription of PDGFRbeta, and that of Ednra and Ednrb, two major receptors in PAH progression. Wound healing and pulmonary artery ring assays indicated that BU inhibited PDGF-induced PASMC migration. BU strongly inhibited PDGF-induced Akt phosphorylation, an effect reversed by the phosphatase inhibitor calyculinA.
In vivo, BU showed efficacy in monocrotaline-induced PAH in rats. Indeed, the HDACi reduced both thickness of distal pulmonary arteries and right ventricular hypertrophy.
Besides these studies, Serial Analysis of Gene Expression (SAGE) has be used to obtain complete transcriptional profiles of peripheral blood mononuclear cells (PBMCs) isolated from PAH and Healthy subjects. SAGE allows quantitative analysis of thousands transcripts, relying on the principle that a short oligonucleotide (tag) can uniquely identify mRNA transcripts. Tag frequency reflects transcript abundance. We enrolled patients naïve for a specific PAH therapy (4 IPAH non-responder, 3 IPAH responder, 6 HeritablePAH), and 8 healthy subjects. Comparative analysis revealed that significant differential expression was only restricted to a hundred of down- or up-regulated genes. Interestingly, these genes can be clustered into functional networks, sharing a number of crucial features in cellular homeostasis and signaling. SAGE can provide affordable analysis of genes amenable for molecular dissection of PAH using PBMCs as a sentinel, surrogate tissue.
Altogether, these findings may disclose novel perspectives in the use of HDACi in PAH and potential biomarkers.
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Dorfmüller, Peter. "RANTES and fractalkine the role of the chemokines in pulmonary arterial hypertension /." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=965026248.
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Abdul, Salam Vahitha Banu. "Application of protein profiling to biomarker discovery in idiopathic pulmonary arterial hypertension." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438975.
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Turner, Joanne L. "Ionic currents in pulmonary arterial smooth muscle and the effect of hypoxia." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360012.
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White, Kevin. "The serotonin transporter, gender and 17 beta estradiol in pulmonary arterial hypertension." Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2582/.
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Pulmonary arterial hypertension (PAH) is a progressive disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The consequence of this is increased pulmonary arterial pressure, right heart failure and eventual death if left untreated. Even in those patients receiving advanced PAH therapy, mortality rates remain high. Therefore, the development of novel therapeutic approaches in the treatment of PAH is urgently required. A better understanding of PAH pathogenesis is critical to achieving this. Gender differences exist in human PAH, with females up to three-fold more likely to present with disease than males. Limited evidence suggests that estrogens may be accountable for these differences. For example, the use of oral contraceptives has been associated with the development of PAH. Paradoxical to this however, experimental models of PAH exhibit male susceptibility which has limited research into the role of estrogens in the pathogenesis of PAH. Serotonin is implicated in both experimental and human PAH. Activity of the serotonin transporter (SERT) modulates the development of PAH and mice over-expressing SERT (SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH. In the central nervous system, estrogens regulate expression of several serotonin signalling components including tryptophan hydroxylase (TPH), the 5-HT receptors and SERT. One hypothesis is that similar estrogen effects on serotonin signalling may also be apparent in the pulmonary vasculature, and this is one hypothesis for the increased female susceptibility observed in PAH. To examine this, the influence of gender and estrogen on the development of PAH in SERT+ mice was investigated. This was repeated following exposure to chronic hypoxia. Pulmonary vascular reactivity was determined using small vessel myography. The genotypic differences in SERT+ mice were also assessed via microarray analysis. Genes of interest were validated by qRT-PCR analysis and immunoblotting. To translate clinical relevance to any findings, the effects of female hormones were also investigated in human pulmonary artery smooth muscle cells (PASMCs) derived from both non-PAH (control) and idiopathic pulmonary arterial hypertension (IPAH) patients. PAH was assessed via measurement of right ventricular systolic pressure (RVSP), pulmonary vascular remodelling and right ventricular hypertrophy (RVH). Male SERT+ mice do not develop PAH. Female SERT+ mice exhibited increased RVSP and pulmonary vascular remodelling. This increased RVSP and pulmonary vascular remodelling were completely prevented following ovariectomy in SERT+ mice. The chronic administration of 17β estradiol (1.5mg/kg/day), which is the pre-dominant circulating female hormone in pre-menopausal women, fully re-established PAH as assessed by increased RVSP and pulmonary vascular remodelling. Pulmonary vascular reactivity to serotonin was unaffected in these mice. In chronic hypoxia, female SERT+ mice exhibited exaggerated hypoxia-induced PAH whereas male SERT+ mice remained unchanged compared to their respective wildtype (WT) controls. This exaggerated hypoxia-induced PAH phenotype was attenuated in SERT+ mice following ovariectomy, as assessed by a reduction in RVSP and pulmonary vascular remodelling. The chronic administration of 17β estradiol completely re-established exaggerated hypoxia-induced PAH in ovariectomized SERT+ mice. Similar to normoxia, serotonin-induced pulmonary vascular contraction was also unaffected in these mice. The stimulation of PASMCs with 17β estradiol increased tryptophan hydroxylase-1, SERT and 5-HT1B receptor expression. Consistent with our in vivo findings, physiological concentrations of 17β estradiol (1nmol/L) stimulated PASMC proliferation whereas estrone, estriol and progesterone had no effect. This proliferation was successfully blocked by both the tryptophan hydroxylase inhibitor para-chlorophenylalanine and the 5-HT1B receptor antagonist SB224289. Microarray analysis in the pulmonary arteries of female SERT+ mice confirmed the dysregulation of multiple pathways with relevance to PAH including those associated with metabolism, cell differentiation and contraction. A large number of PAH-related pathways were also dysregulated in female SERT+ mice exposed to chronic hypoxia. In contrast, pathways were altered in normoxic and chronically hypoxic male SERT+ mice to a much lesser extent. For microarray validation, qRT-PCR analysis was performed in ten selected genes (FOS, CEBPB, CYP1B1, MYL3, HAMP2, LTF, PLN, NPPA, UCP1 and C1S) and 100% concordance was reported. Three genes were selected for further investigation (FOS, CEBPB and CYP1B1). Immunoblotting confirmed that protein expression of c-FOS, C/EBPβ and CYP1B1 was increased in the pulmonary arteries of female SERT+ mice compared against female WT mice. With relevance to human PAH, we also confirmed that mRNA expression of FOS, CEBPB and CYP1B1 was increased in PASMCs derived from IPAH patients. Protein validation with immunoblotting confirmed that c-FOS, C/EBPβ and CYP1B1 expression was also increased in IPAH PASMCs. In summary of these findings, we have identified that females may be at an increased risk to the development of PAH via the effects of 17β estradiol. Specifically, 17β estradiol appears to increase expression of several key serotonin pathway mediators including tryptophan hydroxylase-1 (the rate-limiting enzyme in serotonin synthesis), SERT and the 5-HT1B receptors, all of which have been previously implicated in the pathogenesis of PAH. Our results suggest that 17β estradiol stimulates PASMC proliferation via activation of the serotonin pathway. Microarray analysis in the pulmonary arteries of SERT+ mice confirmed that a large number of genes associated with PAH-related pathways were differentially expressed in females. RNA and protein validation further confirmed these differences in selected genes (CEBPB, CYP1B1 and FOS). With relevance to human PAH, we also confirmed the dysregulation of several key genes at both mRNA and protein level in PASMCs derived from IPAH patients. Taken together, these findings describe the critical role of 17β estradiol in PAH, and this may offer an explanation for the increased susceptibility observed in females.
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Chaudhry, Adil Anthony. "Transient postnatal pulmonary arterial smooth muscle cytoskeletal disassembly and its functional implications." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327049.
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Weir-Mccall, Jonathan. "The role of pulmonary arterial stiffness in right ventricular remodelling in COPD." Thesis, University of Dundee, 2017. https://discovery.dundee.ac.uk/en/studentTheses/e2938aa9-c144-431d-8b0f-ad54bff3c931.
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COPD is the second most common cause of pulmonary hypertension, and is a common complication of severe COPD with significant implications for both quality of life and mortality. Pulmonary arterial stiffening occurs early in the disease process before the development of overt pulmonary hypertension. Early detection would open this up as a potential therapeutic target before end stage arterial remodeling occurs. Traditionally the assessment of the arterial stiffness required right heart catheterization, however recent advance in MRI are yielding new opportunities to undertake this assessment noninvasively. Pulse wave velocity is one of the most commonly used techniques in the systemic circulation but has been poorly explored in the pulmonary circulation. This thesis was undertaken to test the hypothesis that pulmonary PWV would be elevated in COPD, and that this would correlate with right ventricular mass, and predict future adverse remodeling. Two commonly used techniques are available for measuring PWV with MRI: the transit time technique and the flow-area technique. These techniques were applied in a cohort of young healthy volunteers (n=10) and older healthy volunteers (n=20). These techniques were repeated using on-table repetition and repetition at 6 months. These were also assessed during exercise in the young healthy volunteers. PWV did not differ between the two age groups (YHV 2.4±0.3 ms-1, OHV 2.9±0.2 ms-1, p=0.1). Using a high temporal resolution sequence through the RPA using the flow-area technique accounting for wave reflections yielded consistently better within-scan, interscan, intraobserver and interobserver reproducibility. Exercise did not result in a change in PWV (mean (95% CI) of the differences: 0.10 (−0.5 to 0.9), p=0.49) despite a significant rise in heart rate (65±2 to 87±3, p<0.0001), blood pressure (113/68 to 130/84, p<0.0001) and cardiac output (5.4±0.4 to 6.7±0.6 L/min, p=0.004). 58 participants with COPD underwent pulmonary function tests, six-minute walk test, and cardiac MRI. These were compared with a cohort of 20 healthy controls. Cardiac MRI was used to quantify right and left ventricular mass and volumes, with phase contrast imaging of the main pulmonary artery in order to calculate pulmonary PWV and of the ascending and abdominal aorta in order to calculate the aortic pulse wave velocity. Those with COPD demonstrated evidence of pulmonary arterial stiffening and pulmonary vascular remodeling with higher pulmonary artery area at end diastole (COPD: 2.36 ± 0.56 cm2/m1.7 vs. HC: 2.14 ± 0.28 cm2/m1.7, p=0.027), reduced pulsatility (COPD: 24.88 ± 8.84 % vs. HC: 30.55 ± 11.28 %, p=0.021), reduced PAT (COPD: 104.0 ± 22.9 ms vs. HC: 128.1 ± 32.2 ms, p<0.001) and higher PWV (COPD: 2.62 ± 1.29 ms-1 vs. HC: 1.78 ± 0.72 ms-1, p=0.001). Those with an elevated PWV did not demonstrate any difference in subjective breathlessness, exercise capacity, or any difference in right ventricular systolic function. Cardiac remodelling in COPD was instead that of a reduced preload with a lower RV end diastolic volume (COPD: 53.6±11.1 ml vs. HC: 59.9±13.0 ml,p=0.037) and RV stroke volume (COPD: 31.9±6.9 ml/m2 vs. HC: 37.1±6.2 m/m2l,p=0.003). Those with COPD had a nonsignificantly higher aortic PWV (COPD: 8.7 ± 2.7 ms-1 vs. HC: 7.4 ± 2.1 ms-1, p=0.06), with aortic PWV correlating with left ventricular remodeling (rho=0.34, p=0.01). 34 participants with COPD underwent repeat imaging at 1 year. While there was a significant increase in pulmonary PWV (Baseline 2.30 ± 0.97, Follow-up: 3.39 ± 1.4 ms-1, p<0.001) there was no significant change in ventricular mass or volumes. This thesis has therefore proven its original hypothesis that pulmonary PWV is elevated in those with COPD. However we have seen that this elevation in PWV has no significant association with right ventricular remodeling either at baseline or at one-year follow-up. Instead we observed a pattern of ventricular remodeling that was more consistent with an under filled condition rather than an overloaded condition. Future work in COPD should thus be targeted at better understanding of the underpinning pathophysiological process behind this.
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Prabu, Athiveeraramapandian. "Prevalence and risk factors for pulmonary arterial hypertension in patients with lupus." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4195/.
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Background: Pulmonary arterial hypertension (PAH) is a recognised complication of SLE. The risk of developing PAH in SLE may be increased in a subset of patients with antiphospholipid antibodies. Aims: To estimate the point prevalence of PAH, to evaluate screening tests and to identify risk factors for PAH in a large cohort of SLE patients Methods: A prospective cross-sectional study of 288 patients with SLE using resting transthoracic echocardiography to estimate the systolic pulmonary artery pressures (sPAP) and to assess cardiac morphology and function. We assessed potential risk factors such as the presence of lung disease, autoantibodies and anti-phospholipid syndrome (APS). We evaluated screening tests such as pulmonary function tests, six minute walk test and biomarkers. Results: Twelve out of 283 patients had PAH with sPAP >30 mm Hg (range 31-59 mmHg). Only 3 patients had sPAP >40 mm Hg. The only significant risk factor for PAH was lupus anticoagulant (p=0.005). Conclusion: The point prevalence of PAH was 4.2% in our cohort of patients with SLE. The significant association of lupus anticoagulant and presence of APS in PAH cases suggests that thrombosis may play an important role in the development of PAH with SLE patients.
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Lammers, A. E. "Non-invasive evaluation, therapy and transplantation in children with pulmonary arterial hypertension." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1331893/.
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Pulmonary hypertension (PHT) is a progressive and ultimately fatal disease. The condition is poorly understood in children. This thesis evaluated non-invasive assessment techniques, experience with epoprostenol, atrial septostomy and lung transplantation in children. As therapy is guided by patients’ functional capacity, studies focused on 6-minute walk test distance (6MWTd) and cardiopulmonary exercise testing (CPET). Age-related normal values of 6MWTd were determined, and the relationship between 6MWTd and CPET was assessed. Echocardiographic markers of impaired myocardial function were investigated using tissue Doppler (TDI) and potential risk-factors of mortality were sought using heart rate variability (HRV) and B-natriuretic peptide (BNP). Parameters of CPET correlated with 6MWTd in highly compromised children but in less impaired children the 6MWT represented a sub-maximal test, indicating that a CPET is required when 6MWTd exceeds 300m. BNP and HRV were related to prognosis but sensitivity and specificity are limited. TDI demonstrated that biventricular function is impaired in children with PHT and that left ventricular impairment cannot be evaluated adequately using conventional echocardiographic techniques. Reviewing our experience with intravenous epoprostenol, it improved functional capacity, survival and could be used safely in children with acceptable morbidity. Atrial septostomy abolished syncope and improved right ventricular function, at the expense of mild systemic arterial oxygen desaturation. Septostomies, with and without a fenestrated device, can close spontaneously with time, stressing the need for a more reliable device. When medical therapies were exhausted, transplantation dramatically improved quality of life and survival. Listing criteria were shown to have been appropriate but more objective criteria are needed. These studies evaluating assessment techniques, prognosticators, and therapies have given further insight into the management of children with PHT. Future work should include assessment of non-invasive magnetic resonance imaging, exploring a combined prognosticator, combination therapy and improving classification of clinical status to optimise therapy and facilitate trials of new, urgently needed medicines.
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Toshner, Mark. "Studies of endothelial progenitor cells and kinase inhibition in pulmonary arterial hypertension." Thesis, University of Aberdeen, 2011. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=203754.
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Udaya, Hebbar Ullhas. "Evaluating Coupled Hemodynamics and Arterial Wall-Compliance in a Realistic Pulmonary Artery." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1544002380938861.
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Caruso, Paola. "Pulmonary arterial hypertension : role of miRNAs in animal models and pathological samples." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3472/.
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Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries (PAs), characterized by an increase in pulmonary arterial pressure and vascular remodelling leading to a progressive increase in pulmonary vascular resistance. The consequence of vascular obliteration is right heart failure and high mortality. Germline mutations in the gene coding for the bone morphogenetic protein (BMP) type-2 receptor (BMPR2), a receptor for the transforming growth factor (TGF)-beta super-family, have been identified in approximately 70% of patients with the heritable form of PAH (HPAH). Moreover, BMPR2 expression is markedly reduced in PAH cases in the absence of mutations in this gene (idiopathic PAH, IPAH). In pulmonary artery smooth muscle cells (PASMCs) mutations in BMPR2 are associated with an abnormal growth response to BMPs and TGF-beta. In endothelial cells (PAECs), these mutations increase the susceptibility of cells to apoptosis. The absence of BMPR2 mutations in some families and in the majority of IPAH cases suggests that further pathological mechanisms still need to be identified. The serotonin system has also been implicated in both experimental and human PAH. In fact, an additional genetic risk factor for the development of this pathology has been identified in the serotonin transporter (SERT), dysregulated in IPAH patients. Mice over-expressing SERT (SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH. Although different advanced PAH therapies are currently available, they can only provide a symptomatic relief, and mortality rates remain high. Therefore, the identification of novel therapeutic approaches for the treatment of this pathology is urgently required. MicroRNAs (miRNAs) are a class of small, endogenous and non-coding RNAs able to negatively regulate gene expression by targeting specific messenger RNAs (mRNAs) and inducing their degradation or translational repression. These non-coding sequences are transcribed from endogenous loci as long precursors, converted in single-stranded molecules of approximately 20 nucleotides after a series of enzymatic maturation steps. miRNAs carry out their activity in association with the RNA-induced silencing complex (RISC), interacting with the 3’ untranslated region (3’UTR) of specific target mRNAs which they bind with imperfect complementarity. Several recent studies have assessed the direct role of miRNAs in vascular inflammation and in the development of cardiovascular pathologies. The aim of this project was to investigate the role of miRNAs in the development of PAH. In Chapter 3, two distinct and well established rat models (hypoxic and monocrotaline) of PAH were used to determine the regulation of miRNAs during disease initiation and progression. We demonstrate time and insult-dependent changes in a specific group if miRNAs and this dysregulation was also confirmed in vitro in rat and human PA cells exposed to chronic hypoxia. Moreover, the stimulation of rat cells with TGF-beta and BMP4 mimicked the alteration of miRNA expression observed in vivo. An analysis of the expression level of the main enzymes involved in miRNA maturation (i.e. Dicer, Drosha, DGCR8 and Exp5) revealed the significant down-regulation of Dicer in response to chronic hypoxia both in vivo and in vitro, suggesting that the manipulation of this enzyme could re-establish a normal miRNA expression level in pathological samples. We also identified selective targets altered in response to miRNA dysregulation, suggesting the possibility of future interventional studies. In Chapter 4 the specific role of miR-143 and miR-145 in the development of PAH was evaluated. We report the significant up-regulation of these miRNAs in WT mice exposed to chronic hypoxia and that genetic ablation of miR-145 is protective against the development of PAH (with no effects on miR-143 expression), assessed via measurement of systolic right ventricular pressure (sRVP), pulmonary vascular remodelling and right ventricular hypertrophy (RVH). miR-145 KO has also an effect on the expression of specific targets, including kruppel-like factor 4 and 5 (KLF4 and 5), which are regulators of smooth muscle proliferation and differentiation. Further, both miR-143 and miR-145 are up-regulated in mice heterozygous for a BMPR2 mutation. In human tissues we confirm the elevated expression of the miR-143/145 cluster observed in hypoxic mice in pathological samples compared with unaffected controls, suggesting a conserved regulation of these miRNAs in the two species. The study described in this chapter is the first to report a critical role for miR-145 in the development of PAH in vivo. Finally, in Chapter 5 a preliminary study focused on miR-21 regulation and function on PAH development is shown. An analysis of the expression of this miRNA in WT mice revealed its up-regulation in response to chronic hypoxia, whereas the genetic ablation of miR-21 induced an exaggerated hypoxia-induced PAH phenotype. However, the analysis of human pathological samples showed a reduced expression of this miRNA in comparison with unaffected controls, suggesting its differential regulation in hypoxic mice and patients, although the differences observed between the animal and the human pathology could be the cause of this different phenothipe. The identification of dysregulated targets in both the species will give more informations about the effect of miR-21 alteration in the development of PAH. In summary, the results presented in this thesis support a role for defined miRNAs in the development of PAH, both in animal models and patients. Whether this specific alteration of selective miRNAs can be used as a novel therapeutical approach still need to be evaluated, but represent an attractive possibility to assess in the longer term.
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Tamaddon, Houman. "The Simulation of Pulmonary Arterial Vascular System - A Computational Fluid Dynamics Study." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13751.
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Clinical studies suggest that hemodynamic factors and biomechanical forces play key roles in pulmonary vascular disease; any condition which affects the route of blood flow between the heart and lungs. Research in this area that involves simulating large networks of pulmonary vessels using computational fluid dynamics is rare. This is because conventional visualisation techniques such as direct volume rendering and surface rendering using contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI) data fail to resolve the smaller and more extensively networked pulmonary vascular trees or recognise the complex spatial relations of the vascular tree and its surrounding structures in detail. Meanwhile, solutions to the governing equations of blood flow in the large arteries are highly dependent on the outflow boundary conditions imposed to represent the vascular bed downstream of the modelled domain. The most common outflow boundary conditions, especially for threedimensional simulations of blood flow, are prescribed constant pressure or traction and prescribed velocity profiles. In many simulations, however, the flow distribution and pressure field in the modelled domain are unknown and cannot be prescribed at the outflow boundaries. Accurate hemodynamic predictions can only be achieved by creating a model with both a region of interest and the downstream network of vessels that are an accurate reflection of the organ system in question. In this study, we introduce two different approaches to take into account feedback mechanisms of the distal networks in computational simulations.
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Wahl, Joel. "Development of Methods to Investigate Pulmonary Arterial Smooth Muscle Cells under Hypoxia." Licentiate thesis, Luleå tekniska universitet, Strömningslära och experimentell mekanik, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:ltu:diva-77140.
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Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to localized alveolarhypoxia that is intrinsic to the pulmonary circulation. By hypoxia-induced contractionof pulmonary arterial smooth muscle cells (PASMCs), the pulmonary capillary bloodflow is redirected to alveolar areas of high oxygen partial pressure, thus maintaining theventilation-perfusion ratio. Although the principle of HPV was recognized decades agothe underlying pathway remains elusive. The patch clamp technique, imaging and Ramanspectroscopy are methods that can be used to investigate parts of the mechanisms. Toenable measurements at controlled oxygen concentrations a gas-tight microfluidic systemwas developed. In this thesis preparatory experiments to couple the gas-tight systemto a microscope that enabled simultaneous measurements with patch clamp, imagingand Raman spectroscopy are discussed. The patch clamp technique is to be used formeasurements on the dynamics of the ion-channels in the cellular membrane as well aschanges in membrane potential as a response to hypoxia. Imaging of PASMCs is requiredto successfully apply the patch clamp technique. Further, imaging will also reveal whetherthe mechanical response of HPV has been triggered, for this purpose image analysis forestimation of optical flow can be used. Raman spectroscopy enables measurements ofbiochemical changes in redox biomarkers, cytochrome c and NADH, of the mitochondrialelectron transport chain. This thesis shows that the gas-tight microfluidic system providesoptimal control of the oxygen content, in an experimantal setting where the patch clamptechnique can be applied. Raman measurements showed significantly larger variationsin spectra compared to an open fluidic system, which is the conventional approach.However, the results showed a need for improved Raman preprocessing. For this purposea Convolutional Neural Network (CNN) was trained using synthetic spectra that providedoptimal reconstruction of the Raman signal. Finally, simultaneous imaging and Ramanspectroscopy of red blood cells were performed in a home built microscope. The resultspave the way for measurements on PASMCs.
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Ogawa, Eri. "Living-donor liver transplantation for pediatric liver disease with moderate or severe porto-pulmonary hypertension accompanied by pulmonary arterial hypertension." Kyoto University, 2018. http://hdl.handle.net/2433/230973.
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Foster, William Swinburne. "Translationally Controlled Tumour Protein as a Novel Therapeutic Target in Pulmonary Arterial Hypertension." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35006.
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Background: Pulmonary arterial hypertension (PAH) is a multifaceted disease characterized by elevated pulmonary arterial pressure, right ventricular hypertrophy, and a poor prognosis. Pathological hallmarks of PAH include pulmonary vascular remodelling, pre-capillary arterial obliteration, and plexiform lesions. Over the past 15 years, pulmonary endothelial cell (EC) apoptosis has been repeatedly implicated as a key trigger of occlusive arterial remodelling in PAH. While it has been hypothesized that pulmonary EC apoptosis gives rise to the emergence of growth-dysregulated, apoptosis- resistant ECs involved in arterial remodelling, the molecular mechanisms linking these two events has not yet been fully elucidated. Recently, our lab identified translationally controlled tumour protein (TCTP) as one of several significantly dysregulated proteins in culture-derived blood-outgrowth endothelial cells (BOECs) isolated from hereditable PAH (HPAH) patients harbouring mutations in the gene encoding for bone morphogenetic protein receptor type 2. Immunohistological analyses indicated that TCTP expression was associated with intra-luminal pulmonary ECs and inflammatory cells in the remodelled vessels of both human PAH patients and SU5416 rats. Furthermore, TCTP silencing abrogated excessive HPAH BOEC proliferation and promoted apoptosis in vitro. Hypothesis: We hypothesized that TCTP represents a central molecular mechanism linking pulmonary arterial EC damage and apoptosis to the emergence of growth- dysregulated lung vascular cells and complex arterial remodelling in PAH.Purpose: The purpose of the present thesis was to examine the effects TCTP inhibition on EC survival and TCTP abundance in vitro as well as on pulmonary hemodynamic changes and arterial remodelling in vivo using a well-validated rat model of severe PAH. Methods: Inhibition of TCTP was accomplished using two TCTP small molecule inhibitors, sertraline and thioridazine. In vitro, rat lung microvascular ECs (RLMVECs) were exposed to thioridazine and assayed for TCTP abundance, survival, and markers of apoptosis. In vivo, PAH was induced in male Sprague Dawley rats using SU5416 combined with 3 weeks of chronic hypoxia (SU/CH). After 4 weeks, right ventricle systolic pressure (RVSP) was measured by direct catheterization and osmotic pumps containing either thioridazine or sertraline were implanted subcutaneously. Following 3 weeks of small molecule delivery, RVSP was re-evaluated, cardiac function/structure was determined using transthoracic echocardiography, and histological analyses of vascular remodelling and inflammation were performed. Results: Our in vitro experiments demonstrated that thioridazine was able to significantly down-regulate TCTP levels and induce an apoptotic phenotype in RLMVECs. In the SU/CH rat model of severe PAH, both thioridazine and sertraline failed to have any effect on pulmonary hemodynamics, right ventricle structure/function, or vascular remodelling. Moreover, neither small molecule was able to detectably down-regulate TCTP levels in the lungs of SU/CH rats. Immunofluorescence staining revealed that TCTP expression occasionally corresponded with the expression of macrophage/monocyte marker CD68 in the lungs of SU/CH rats, consistent with its expression by inflammatory cells; however, no significant differences were found in adventitial cell clearance in the presence or absence of the inhibitors. Conclusions: Our findings support previous reports that thioridazine is able to significantly down-regulate TCTP and induce apoptosis in vitro. In contrast, both small molecule inhibitors failed to down-regulate lung TCTP levels or have any beneficial effects on the progression of PAH in SU/CH rats.
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Yelle, Dominique. "The role of apoptosis in a BMPR2 mutant model of pulmonary arterial hypertension." Thesis, University of Ottawa (Canada), 2011. http://hdl.handle.net/10393/28916.
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Pulmonary arterial hypertension (PAH) is a rare and fatal disease caused by excessive remodelling of small pulmonary arterioles. Heterozygous loss-of-function mutations in the bone morphogenetic protein receptor 2 (BMPR2) have recently been identified in a large portion of patients with familial and idiopathic PAH. However, how mutations in this ubiquitously expressed receptor result in such a specific abnormality of the lung microcirculation is unknown. We hypothesized that loss-of-function mutations in BMPR2 lead to PAH by increasing the susceptibility of ECs to apoptosis, particularly within fragile pulmonary arterioles. To examine the consequences of BMPR2 mutations on the development of PAH, we generated mice that ubiquitously over-express an arginine to stop mutation in the receptor's C-terminal domain (BMPR2 R899X) Characterization of these mice revealed a significant increase in right ventricular systolic pressure, an indicator of pulmonary pressure, which was associated with muscularization of small pulmonary arterioles, alveolar septal thickening and pulmonary macrophage infiltration. In addition, a modest increase in apoptosis was detected in these mice. These data suggest that BMPR2 loss-of-function mutations increase the susceptibility of ECs to apoptosis and set the stage for excessive inflammation, possibly leading to spontaneous PAH. This new model will help elucidate the pathophysiological events leading to the development of PAH and provide a unique tool to evaluate novel potential treatments for this disease.
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Pullamsetti, Soni [Verfasser]. "Role of dimethylarginine dimethylaminohydrolases (DDAH) in pulmonary arterial hypertension / vorgelegt von Soni Pullamsetti." Giessen : VVB Laufersweiler, 2006. http://d-nb.info/98866240X/34.
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Lu, Changwu [Verfasser]. "Antifibrotic drugs: new candidates for the treatment of pulmonary arterial hypertension? / Changwu Lu." Gießen : Universitätsbibliothek, 2018. http://d-nb.info/1163533688/34.
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Deng, Lin. "The role of non-coding RNA in the development of pulmonary arterial hypertension." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7828/.
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Pulmonary arterial hypertension (PAH) is a progressive disease of the small pulmonary arteries, characterised by pulmonary vascular remodelling due to excessive proliferation and resistance to apoptosis of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs). The increased pulmonary vascular resistance and elevated pulmonary artery pressures result in right heart failure and premature death. Germline mutations of the bone morphogenetic protein receptor-2 (bmpr2) gene, a receptor of the transforming growth factor beta (TGF-β) superfamily, account for approximately 75%-80% of the cases of heritable form of PAH (HPAH) and 20% of sporadic cases or idiopathic PAH (IPAH). IPAH patients without known bmpr2 mutations show reduced expression of BMPR2. However only ~ 20% of bmpr2-mutation carriers will develop the disease, due to an incomplete penetrance, thus the need for a ‘second hit’ including other genetic and/or environmental factors is accepted. Diagnosis of PAH occurs most frequently when patients have reached an advanced stage of disease. Although modern PAH therapies can markedly improve a patient’s symptoms and slow the rate of clinical deterioration, the mortality rate from PAH remains unacceptably high. Therefore, the development of novel therapeutic approaches is required for the treatment of this multifaceted disease. Noncoding RNAs (ncRNAs) include microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). MiRNAs are ~ 22 nucleotide long and act as negative regulators of gene ex-pression via degradation or translational inhibition of their target mRNAs. Previous studies showed extensive evidence for the role of miRNAs in the development of PAH. LncRNAs are transcribed RNA molecules greater than 200 nucleotides in length. Similar to classical mRNA, lncRNAs are translated by RNA polymerase II and are generally alternatively spliced and polyadenylated. LncRNAs are highly versatile and function to regulate gene expression by diverse mechanisms. Unlike miRNAs, which exhibit well-defined actions in negatively regulating gene expression via the 3’-UTR of mRNAs, lncRNAs play more diverse and unpredictable regulatory roles. Although a number of lncRNAs have been intensively investigated in the cancer field, studies of the role of lncRNAs in vascular diseases such as PAH are still at a very early stage. The aim of this study was to investigate the involvement of specific ncRNAs in the development of PAH using experimental animal models and cell culture. The first ncRNA we focused on was miR-143, which is up-regulated in the lung and right ventricle tissues of various animal models of PH, as well as in the lungs and PASMCs of PAH patients. We show that genetic ablation of miR-143 is protective against the development of chronic hypoxia induced PH in mice, assessed via measurement of right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH) and pulmonary vascular remodelling. We further report that knockdown of miR-143-3p in WT mice via anti-miR-143-3p administration prior to exposure of mice to chronic hypoxia significantly decreases certain indices of PH (RVSP) although no significant changes in RVH and pulmo-nary vascular remodelling were observed. However, a reversal study using antimiR-143-3p treatment to modulate miR-143-3p demonstrated a protective effect on RVSP, RVH, and muscularisation of pulmonary arteries in the mouse chronic hypoxia induced PH model. In vitro experiments showed that miR-143-3p overexpression promotes PASMC migration and inhibits PASMC apoptosis, while knockdown miR-143-3p elicits the opposite effect, with no effects observed on cellular proliferation. Interestingly, miR-143-3p-enriched exosomes derived from PASMCs mediated cell-to-cell communication between PASMCs and PAECs, contributing to the pro-migratory and pro-angiogenic phenotype of PAECs that underlies the pathogenesis of PAH. Previous work has shown that miR-145-5p expression is upregulated in the chronic hypoxia induced mouse model of PH, as well as in PAH patients. Genetic ablation and pharmacological inhibition (subcutaneous injection) of miR-145-5p exert a protective against the de-velopment of PAH. In order to explore the potential for alternative, more lung targeted delivery strategies, miR-145-5p expression was inhibited in WT mice using intranasal-delivered antimiR-145-5p both prior to and post exposure to chronic hypoxia. The decreased expression of miR-145-5p in lung showed no beneficial effect on the development of PH compared with control antimiRNA treated mice exposed to chronic hypoxia. Thus, miR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while the inhibition of miR-143-3p prevented the development of experimental pulmonary hypertension. We focused on two lncRNAs in this project: Myocardin-induced Smooth Muscle Long noncoding RNA, Inducer of Differentiation (MYOSLID) and non-annotated Myolnc16, which were identified from RNA sequencing studies in human coronary artery smooth muscle cells (HCASMCs) that overexpress myocardin. MYOSLID was significantly in-creased in PASMCs from patients with IPAH compared to healthy controls and increased in circulating endothelial progenitor cells (EPCs) from bmpr2 mutant PAH patients. Exposure of PASMCs to hypoxia in vitro led to a significant upregulation in MYOSLID expres-sion. MYOSLID expression was also induced by treatment of PASMC with BMP4, TGF-β and PDGF, which are known to be triggers of PAH in vitro. Small interfering RNA (siR-NA)-mediated knockdown MYOSLID inhibited migration and induced cell apoptosis without affecting cell proliferation and upregulated several genes in the BMP pathway in-cluding bmpr1α, bmpr2, id1, and id3. Modulation of MYOSLID also affected expression of BMPR2 at the protein level. In addition, MYOSLID knockdown affected the BMP-Smad and BMP-non-Smad signalling pathways in PASMCs assessed by phosphorylation of Smad1/5/9 and ERK1/2, respectively. In PAECs, MYOSLID expression was also induced by hypoxia exposure, VEGF and FGF2 treatment. In addition, MYOSLID knockdown sig-nificantly decreased the proliferation of PAECs. Thus, MYOSLID may be a novel modulator in pulmonary vascular cell functions, likely through the BMP-Smad and –non-Smad pathways. Treatment of PASMCs with inflammatory cytokines (IL-1 and TNF-α) significantly in-duced the expression of Myolnc16 at a very early time point. Knockdown of Myolnc16 in vitro decreased the expression of il-6, and upregulated the expression of il-1 and il-8 in PASMCs. Moreover, the expression levels of chemokines (cxcl1, cxcl6 and cxcl8) were sig-nificantly decreased with Myolnc16 knockdown. In addition, Myolnc16 knockdown decreased the MAP kinase signalling pathway assessed by phosphorylation of ERK1/2 and p38 MAPK and inhibited cell migration and proliferation in PASMCs. Thus, Myolnc16 may a novel modulator of PASMCs functions through anti-inflammatory signalling pathways. In summary, in this thesis we have demonstrated how miR-143-3p plays a protective role in the development of PH both in vivo animal models and patients, as well as in vitro cell cul-ture. Moreover, we have showed the role of two novel lncRNAs in pulmonary vascular cells. These ncRNAs represent potential novel therapeutic targets for the treatment of PAH with further work addressing to investigate the target genes, and the pathways modulated by these ncRNAs during the development of PAH.