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1
Calvert, Patrick Andrew. "Virtual-histology intravascular ultrasound in vulnerable atherosclerosis." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609857.
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McCord, Barbara Norton. "Fatigue of atherosclerotic plaque." Diss., Georgia Institute of Technology, 1992. http://hdl.handle.net/1853/15890.
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Dennis, Maxine Elizabeth. "Oestrogen and atherosclerosis." University of Western Australia. School of Pathology and Laboratory Medicine, 2009. http://theses.library.uwa.edu.au/adt-WU2009.0134.
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[Truncated abstract] Our understanding of the actions of oestrogen on the vasculature has recently been questioned following the results of large clinical trials revealing a negative effect of hormone replacement therapy (HRT) on cardiovascular disease (CVD) risk amongst postmenopausal women. It is important to determine how a hormone with numerous positive effects on intermediate pathways of atherosclerosis fails to offer cardioprotection. Further investigation into the actions of oestrogen in the vasculature may add to our current understanding of the pathogenesis of atherosclerosis and oestrogen biology. The primary aim of this thesis was to investigate involvement of the oestrogen receptors (ERs) in atherosclerotic CVD and to provide further insight into the actions of oestrogen on the vasculature by studying the actions of oestrogen on the regulation of an oestrogen-responsive gene within human vascular cells. Following confirmation of ERa and ERß expression at the RNA and protein level in human aorta sections, correlations of receptor expression with age and atherosclerosis were examined. Significantly strong negative relationships of ERa, androgen receptor (AR), and progesterone receptor (PR) with age in both males and females were detected. No trend was detected between ERß expression and age. These findings suggest that the receptor-mediated actions of hormones in the vasculature may change with age. Further, this thesis compared for the first time sex hormone receptor expression in normal and adjacent atherosclerotic aortic tissue providing a critical assessment of receptor differences due to atherosclerosis. Results revealed reductions of all hormone receptors in early atherosclerotic versus normal aorta tissue. ... These results suggest that the 3'-UTR SNPS may have more of an influence on carotid thickening when oestrogen levels are lower, suggesting the importance of both genetic variation of the ERß gene and oestrogen status on carotid thickening. Finally, this was the first study to investigate oestrogen-induced regulation of angiotensinogen (AGT), a candidate gene for CVD, in human vascular cells. Oestrogen influenced AGT transcription in a cell specific manner. The overall influence of oestrogen on AGT transcription in the vasculature is unknown. This thesis adds to the knowledge of oestrogen and atherosclerosis by suggesting the involvement of the sex hormone receptors (ERa, ERß, PR and AR) in atherosclerosis, presenting ERß as a potentially important candidate gene for atherosclerosis, revealing interactions between estrogen status and associations of ERß SNPs with carotid thickening, and demonstrating vascular cell-specific actions of oestrogen on the regulation of a candidate gene for CVD. These factors may have contributed to the lack of cardio-protection following HRT, as revealed by large clinical trials.
4
Jatta, Ken. "Inflammation in Atherosclerosis." Doctoral thesis, Örebro : Universitetsbiblioteket, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-478.
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Shakya, Arvind. "Mechanism of matrix metalloproteinase-14 (mmp-14) regulation during atherosclerosis." Diss., Columbia, Mo. : University of Missouri-Columbia, 2006. http://hdl.handle.net/10355/4436.
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Thesis (Ph. D.)--University of Missouri-Columbia, 2006.<br>"December 2006" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.
6
Crisby, Milita. "Cell death in atherosclerosis /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3191-7/.
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Ahmed, Ejaz. "Immune mechanisms in atherosclerosis /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4612-4/.
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Arno, Gavin. "Chlamydia Pheunomiae and atherosclerosis." Thesis, St George's, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498342.
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Kharbanda, Rajesh Kumar. "Endothelial dysfunction in atherosclerosis." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409090.
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Alissa, Eman Mokbel. "Micronutrient status and atherosclerosis." Thesis, University of Surrey, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419967.
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Johnson-Tidey, Ruth R. "Monocyte adhesion in atherosclerosis." Thesis, King's College London (University of London), 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387903.
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Falck-Hansen, Mika André. "Macrophage regulation in atherosclerosis." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/29863.
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Atherosclerosis is the leading cause of cardiovascular disease, topping the mortality list in the United Kingdom and the rest of the world. Macrophage activation and polarisation are key steps in host defence and chronic inflammatory diseases, including atherosclerosis. The myeloid glycoprotein receptor CD200R1 belongs to a family of four isoforms and signals after binding to its cognate ligand, CD200. The CD200/CD200R1 interaction blocks pro-inflammatory cytokines and has never before been studied in atherosclerosis. My work has demonstrated that CD200R is weakly expressed in atherosclerotic lesions during disease progression and significantly down-regulated in secondary lymphoid organs. Moreover, changes in shear stress had no effect on the expression of CD200R in plaques. During the steady state, the expression of CD200R on circulating monocytes was highest on the CD11b+CD115+Ly6Cint subset, revealing a potential mechanism for regulation of maturing monocytes. In vitro studies demonstrated that CD200R expression is sensitive to M1 macrophage polarising cytokine IFN-γ and MyD88-dependent TLR ligands. In contrast, non-MyD88-dependent TLR3 signalling had no effect on its expression, supporting previous findings in the literature. Moreover, CD200R1 mRNA expression was induced on alternatively activated M2a macrophage subsets following IL-4 and IL-13 cytokine treatment, whereas oxLDL had no effect. Immunotherapy with CD200-Fc in ApoE-/- mice exerted no significant changes on lesion size and phenotype compared to controls after nine weeks. My findings indicate that the type of inflammatory stimulus may play a role in dictating the ability of myeloid cells to terminate their own activation via CD200/CD200R1 signalling. Hence, chronic inflammation may be promoted by reduced presence of inhibitory signals leading to sustained, unresolved inflammation. In summary, my work has revealed new insight into the regulation of the inhibitory CD200R pathway in atherosclerosis, the molecular signals that may affect the regulation of inflammation through CD200R and possible future therapeutic strategies.
13
Yaremenko, B., Марина Миколаївна Дунаєва, Марина Николаевна Дунаева, and Maryna Mykolaivna Dunaieva. "Modern look at atherosclerosis." Thesis, Sumy State University, 2020. https://essuir.sumdu.edu.ua/handle/123456789/78062.
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It is known that Atherosclerosis is one of the major cause of mortality in our time, but despite this, the exact therapy and pathogenesis have not been developed. This pathology is caused by local changes of the vascular wall and general disorders of lipid metabolism that cause lipoidosis of the inner lining of the arteries. With slow stenosis of the arteries, there is a gradual replacement of the functional tissue to the connective tissue, which leads to myocardial infarction, ischemic stroke or hypertrophy. Science doesn’t know how to stay and always move from one point to another, so recent studies by Kiss-Toth and Johnston show that the TRIB1 protein (Tribbles pseudokinase 1), which is present in macrophages, increases the number of receptors for LDL, which promotes the development of the disease. Also other researchers have found a correlation between atherosclerosis and thyroxine levels in the blood, suggesting that measuring thyroid hormones may help identify patients at risk of atherosclerosis.
14
Chalmers, Alexander David. "Mathematical Modelling of Atherosclerosis." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14986.
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In atherosclerosis, the arterial lining undergoes a specific sequence of inflammatory responses to an injury to the cells that line the blood vessel and to low density lipoprotein (LDL) particles from the blood stream that penetrate through this injury into the arterial wall. We model the events that take place inside the blood vessel wall that occur immediately after such an injury with a system of partial differential equations that involve the LDL particles, two proinflammatory cytokines, monocyte-derived macrophages and their lipid-filled counterparts, foam cells. The model includes the chemical and physical interactions with the endothelial cells that line the arterial wall. These interactions are formulated as boundary conditions. Through numerical simulations, we show that different LDL concentrations in the blood stream and different immune responses can qualitatively affect the development of a plaque. Numerical bifurcation analysis at the quasi-steady state through AUTO shows that there exists of a fold bifurcation when the flux of LDL into the plaque from the blood is high. An atherosclerotic plaque that develops within the intima, deforms the intima locally as macrophages and foam cells accumulate. We model the structure of the developing plaque by cell pressure and cell sorting models to account for the limited space within the intima. We do this by modelling cell movement in crowded tissue in a discrete space and extend this to a spatial domain where cells also moves due to cell pressure and chemotaxis. We model the mechanics of the physical interactions on the two bounding interfaces, (the lumen-intima boundary and the intima-media boundary) and of the tissue inside the domain and add advective terms to ensure that the mechanics of the cellular species is consistent with the underlying tissue deformation. Using a finite element solver, we produce numerical results in one dimension across the intima and in two dimensions as a cross section of an artery. With appropriate parameter values, this moving boundary problem produces results in agreement with the current theory on compensatory enlargement in atherosclerotic remodelling
15
Song, Hannah. "Endothelial bone morphogenic protein 4 and bone morphogenic protein receptor II expression in inflammation and atherosclerosis." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/28258.
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Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2008.<br>Committee Chair: Hanjoong Jo; Committee Member: Ajit P. Yoganathan; Committee Member: Andrew P. Kowalczyk; Committee Member: David G. Harrison; Committee Member: Kathy K. Griendling
16
Poupel, Lucie. "Rôle des chimiokines dans la mobilisation monocytaire au cours de l’athérosclérose." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T032/document.
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: L’athérosclérose est une maladie inflammatoire chronique des grosses artères à localisation intimale. Elle est probablement la résultante d’une réaction inflammatoire mal contrôlée ayant pour but initial d’éliminer l’accumulation anormale de lipides au niveau de l’intima. Cette élimination est exercé par les monocytes/macrophages, dont l’infiltration et l’accumulation au niveau des lésions sont une étape cruciale de l’inflammation chronique locale provoquant en particulier la production de cytokines.Les mécanismes moléculaires responsables de cette accumulation monocytaire impliquent notamment les chimiokines et leurs récepteurs, acteurs clés de la mobilisation des leucocytes. Les souris génétiquement invalidées pour certaines chimiokines comme CCL2 et CX3CL1 ou pour leurs récepteurs respectifs sont partiellement protégées de l’athérosclérose. Par ailleurs, chez l’homme, des variations génétiques de CX3CR1 sont associées à une réduction du risque d’accidents cardiovasculaires. L’ensemble de ces résultats indiquent un rôle clé des chimiokines inflammatoires dans l’athérogenèse.L’objectif de cette thèse était de tester l’utilisation d’inhibiteurs des récepteurs de chimiokines comme outils thérapeutiques contre l’athérosclérose. Dans ce but, notre laboratoire a développé une molécule aux propriétés antagonistes du récepteur CX3CR1, marqueur utilisé pour la caractérisation phénotypique des monocytes. Nos travaux sur deux modèles murins d’athérosclérose mettent en évidence que le blocage de CX3CR1 par notre antagoniste réduit la taille des plaques d’athérosclérose formées sans modifier leur composition cellulaire ni le taux de cholestérol plasmatique circulant. Cette diminution est corrélée à une diminution du nombre d’une sous-population monocytaire circulante spécifique, ainsi qu’à une diminution de leurs propriétés d’adhérence et de survie. D’un point de vue curatif, l’antagoniste de CX3CR1 est capable de limiter la progression des plaques d’athérosclérose sans la prévenir totalement.L’utilisation d’un outil ciblant spécifiquement le récepteur CX3CR1 nous à permis d’une part de mieux comprendre le rôle de ce dernier dans les processus de monocytose et d’athérogenèse et d’autres part d’évaluer la faisabilité d’approches thérapeutiques visant à limiter le nombre de monocytes infiltrant les lésions d’athérosclérose. Les perspectives de ces travaux consistent d’une part à approfondir encore le rôle de CX3CR1 dans la mobilisation monocytaire, notamment au niveau de la moelle osseuse, et d’autre à utiliser l’antagoniste testé en association avec d’autres drogues ciblant les récepteurs de chimiokines impliqués dans l’athérogenèse, tels que CCR2 et CCR5<br>Atherosclerosis account for nearly 30% of death in industrialized countries. It is a chronic inflammatory disease of the large arteries intima. It has been suggested that it is the result of an uncontrolled inflammatory reaction secondary to an abnormal accumulation of lipids in the intima. The lipid clearance is performed by monocytes / macrophages, Their infiltration and accumulation in atherosclerotic lesions is a critical step of a local chronic inflammation associated with an increased production of cytokines. The molecular mechanisms of the generation of atherosclerotic lesions involve monocytes, chemokines and their receptors which are key players controlling leukocytes mobilization. Mice genetically invalidated for chemokines such as CCL2 and/or CX3CL1 or their respective receptors are partially protected from atherosclerosis. Furthermore, in humans, genetic polymorphisms of CX3CR1 are associated with a reduced risk of cardiovascular events. Taken together, these results highlight a key role for inflammatory chemokines in atherogenesis. The aim of this thesis was to investigate wether inhibitors of chemokine receptors could play a role as therapeutic tools against atherosclerosis. To this end, our laboratory had developed an antagonist of CX3CR1, a crucial phenotypic and functional marker of monocytes. Our work, on two murine models of atherosclerosis, demonstrates that blocking CX3CR1 by our antagonist reduces the size of atherosclerotic lesions. This decrease is correlated with a lower number of circulating inflammatory monocytes, as well as a decrease in their adhesion and survival properties. Therefore, CX3CR1 antagonist coud be able to limit the progression of atherosclerotic plaques. Targeting CX3CR1 allowed us to understand the role of this receptor in the pathophysiology of atherogenesis by its effects on circulating inflammatory monocytes and to evaluate the feasibility of the use of this antagonist as a therapeutic tool to reduce atherosclerotic lesions. Perspectives of this work are firstly to deepen the role of CX3CR1 in monocyte mobilization, especially from the bone marrow, and secondly to test this antagonist in combination with others drugs targeting chemokine receptors involved in atherogenesis, such as CCR2 and CCR5 in order to better control the evolution of atherosclerotic lesions
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Williams, Michelle (Michelle Wing Yin). "The effect of the microenvironment on monocyte differentiation in an atherosclerotic setting using an in vitro model." Thesis, The University of Sydney, 2010. https://hdl.handle.net/2123/28892.
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Atherosclerosis is characterised by the formation of plaques which are composed
of a lipid core and a fibrous cap. Pivotal cells in plaque formation are monocytes, which
are traditionally known for their ability to engulf excess lipids to become foam cells, a
component of the lipid core. In contrast, the principal cells identified in the fibrous cap
are SMCs/SM like cells. The potential of a plaque to rupture is determined by its stability
which in turn is determined by the ratio of the lipid core to fibrous cap. The rupture of a
plaque ultimately leads to heart attacks and strokes often resulting in death.
Recently, however, the ability of monocytes to differentiate into other cells has
been widely reported in the literature. Monocytes have been shown to differentiate into
adipocytes, cardiomyocytes, epidermal cells, fibrocytes, hepatocytes, neurogenic cells,
osteoclasts and T cells. In lieu of these findings the ability of monocytes to differentiate
into SMCs/SM like cells was investigated.
Environmental conditions were found to play a major role in determining
monocytes differentiation. A number of different culture conditions to induce monocyte
differentiation into SMCs/SM like cells were trialled. SMCs/SM like cells were
successfully obtained when monocytes were co-cultured with human coronary aortic
smooth muscle cells (M+SMCs) and human platelets (M+Ps) separated by a 0.4 um
pore. The differentiated cells expressed a number of SMC markers and genes (OLSM
actin, calponin, NMMHC and SM220L) as shown by immunofluorescence staining and
qPCR.
A CD array analysis of the co-cultured cells was performed and it was shown that
these cells had marker expression profiles that discriminated them from monocytes,
macrophages and foam cells. The most notable markers found to be expressed by
M+SMCs were CD13 and by M+Ps CD13, CD29 and CD81, markers which overlapped
with fibroblast and mesenchymal cells.
To show if the monocytes had differentiated into SMCs/SM like cells electron
microscopy was used to study the ultrastructures of these cells. In both M+SMCs and
M+Ps there were microfilaments and increased amounts of rough endoplasmic reticulum
suggesting the differentiation of monocytes not to a SMC but to a SM like cell, a
fibroblast.
In conclusion, this study has shown that given the appropriate environmental
conditions monocytes can differentiate into SM like cells thereby contributing to cap
formation and plaque stability. Therefore, monocytes may play a dual role in the
development of plaque formation and thus, atherosclerosis.
18
Zhou, Xinghua. "Immune mechanisms in atherosclerosis : the role of T cells in murine models of atherosclerosis /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4217-X/.
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Hyder, Joseph Anthony. "Systemic atherosclerosis and bone density." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3211934.
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Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2006.<br>Title from first page of PDF file (viewed June 21, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 121-139).
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Wågsäter, Dick. "CXCL16 and CD137 in Atherosclerosis." Doctoral thesis, Örebro University, Institutionen för vårdvetenskap och omsorg, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-115.
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<p>Atherosclerosis is a progressive inflammatory disease that is characterized by the accumulation of lipids, infiltrated cells and fibrous elements in large arteries.</p><p>This thesis focuses on the molecular mechanisms behind foam cell formation and inflammation, two central processes in the development of atherosclerosis. More specific, we studied the effects of proinflammatory cytokines on CXCL16 expression and its role as scavenger receptor on macrophages and smooth muscle cells in atherogenesis. CXCL16 is defined as a chemokine and a scavenger receptor, regulating adhesion and chemoattraction of CXCR6 expressing cells and uptake of oxLDL. We show that the expression of CXCL16 and its receptor CXCR6 are more pronounced in human atherosclerotic lesions compared with non-atherosclerotic vessels. Increased expression of CXCL16 was also seen in atherosclerotic aortas of apoE-/- mice compared with aortas of non-atherosclerotic, age-matched C57BL/6 mice. In vitro, IFN gamma induced CXCL16 expression in primary human monocytes and smooth muscle cells which resulted in an increased uptake of oxLDL. Treatment of mice with IFN gamma also induced CXCL16 expression in atherosclerotic lesions. Thus, we have demonstrated a role for IFN gamma in foam cell formation through upregulation of CXCL16. The expression of CXCR6 was defined to the same regions as for CXCL16 in the lesion, indicating the presence of cells able to respond to CXCL16. Consequently, CXCL16 could serve as a molecular link between lipid metabolism and immune activity in atherosclerotic lesion.</p><p>CD137 belongs to the TNF family and mediates several important processes in inflammation. CD137 is involved in the activation of T cells, NK cells, B cells and monocytes and regulate cytokine production, proliferation and apoptosis in these cells. A limited number of studies have demonstrated CD137 expression on smooth muscle cells and endothelial cells. Our results show that CD137 mRNA is higher expressed in human atherosclerotic lesions compared with unaffected vessels. We found that endothelial cells express CD137 in atherosclerotic lesions and that cultured endothelial cells and smooth muscle cells express CD137 and CD137 ligand in vitro. CD137 was regulated differentially by proinflammatory cytokines (i.e. IFN gamma, TNF alpha, IL-1 beta) and bacterial lipopolysaccharide depending on cell type. Furthermore, we investigated the effects of CD137 signalling, demonstrating that binding of the CD137 ligand to its receptor increases proliferation and migration of smooth muscle cells.</p><p>In summary, this thesis has focused on the expression, regulation and role of CXCL16 and CD137, two genes that have not been described earlier in the concept of atherosclerosis. The findings demonstrate some of the molecular mechanisms involved in vascular inflammation and may increase our knowledge about the development of atherosclerosis.</p>
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Högberg, Dominika. "Screening for asymptomatic carotid atherosclerosis." Doctoral thesis, Uppsala universitet, Kärlkirurgi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-328803.
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Ischemic stroke is the most common cause of handicap in adults and the third most common cause of death in Sweden. Internal carotid artery atherosclerosis is an important cause and accounts for 20% of ischemic strokes. Screening for carotid atherosclerosis has been debated over the past two decades. The aims of this thesis were (I) to study the prevalence of and risk factors associated with carotid artery atherosclerosis among 65 year old men, (II) to evaluate a simplified ultrasound protocol (the grayscale/mosaic method) for the exclusion of significant carotid artery stenosis for screening purpose, (III) to evaluate the required effect of primary preventive therapy in reducing risk of stroke among patients with asymptomatic carotid disease in order for screening to be cost-effective and (IV) to study natural history of carotid atherosclerosis and outcome five years after screening in 65-year old men. The prevalence of atherosclerotic plaques was high (25%), while the prevalence of >50% stenosis was relatively low (2.0%). Smoking, hypertension, diabetes mellitus and coronary artery disease were independent risk factors and individuals with several risk factors had a higher prevalence of stenosis. Most of those at risk were not on any preventive medication. A simplified grayscale/mosaic method was found to have a high negative predictive value for significant carotid stenosis. The minimum stroke risk reduction effect required for preventive intervention to be cost effective was 22%. Carotid atherosclerotic plaque and stenosis 50-79% has a relatively benign development during five years if treated with BMT and risk factor adjustment. Very few progressed to symptomatic disease. More severe stenosis (80-99%) had higher rate of neurological events, and may benefit from additional intervention. In conclusion, prevalence of silent atherosclerotic disease in carotid arteries was common among 65-year-old men. Most of those at risk had no secondary prevention. There is a simple DUS method that could be used for screening purpose. Screening for carotid disease is only cost-effective if the preventive strategy lowers the risk of stroke by 22%. Men with plaques and moderate stenosis have a good prognosis, but among those with severe stenosis there is a need for further intervention.<br>Screening for asymptomatic carotid atherosclerosis
22
Rip, Jacob. "Lipoprotein lipase, hypertriglyceridemia and atherosclerosis." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2006. http://dare.uva.nl/document/28665.
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Schwartz, Colin J. "Atherosclerosis and occlusive arterial disease /." Title page, contents and foreword only, 1994. http://web4.library.adelaide.edu.au/theses/09SD/09sds399.pdf.
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Parums, D. V. "Studies on inflammation in atherosclerosis." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235059.
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A spectrum of chronic inflammation is commonly seen in association with advanced human atherosclerosis. This local complication of advanced atherosclerosis is termed '<i>chronic periaortitis</i>'. This may be seen sub-clinically in necropsy samples or may present clinically, in more severe cases, as the conditions previously termed 'idiopathic retroperitoneal fibrosis', 'inflammatory aneurysm' or 'peri-aneurysmal retroperitoneal fibrosis'. The inflammatory cells consist of lymphocytes and plasma cells. Thinning or breaching of the media is common to all forms. A histological survey of necropsy material and surgical material has confirmed the unifying concept of chronic periaortitis. Histochemical, immunohistochemical, immunofluorescence and electron microscopy have been used in this study to examine the nature of the inflammatory response. Locally activated B lymphocytes are stimulated to produce immunoglobulin, predominantly IgG, to oxidised low density lipoprotein (LDL) and ceroid elaborated with human atheroma. T helper lymphocytes and HLA-DR positive cells mediate this response. These findings have been confirmed using <i>in vitro</i> culture of lymphocytes derived from tissue and peripheral blood of patients with chronic periaortitis. Antibodies to oxidized LDL and ceroid have been detected in serum from patients with chronic periaortitis using a modified ELISA technique. This has led to the development of a potential diagnostic test for chronic periaortitis. These results support the hypothesis that chronic periaortitis has an auto-allergic cause and that the allergen is a component of ceroid, likely to be oxidized LDL, elaborated in human atherosclerotic plaques.
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Ramshaw, Anna Louise. "Immunological aspects of human atherosclerosis." Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305549.
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Lindsay, Alistair. "Magnetic resonance imaging of atherosclerosis." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526491.
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Smith, Cheryl. "Reactive oxygen species in atherosclerosis." Thesis, King's College London (University of London), 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302549.
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Hegyi, Laszlo. "Macrophage apoptosis and human atherosclerosis." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627017.
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Smith, Dr David Andrew. "Chlamydia pneumoniae infection and atherosclerosis." Thesis, University of London, 2004. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539377.
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Qing, Hua. "TELOMERASE REVERSE TRANSCRIPTASE IN ATHEROSCLEROSIS." UKnowledge, 2017. http://uknowledge.uky.edu/pharmacol_etds/19.
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Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase and the limiting factor for the enzyme activity. The expression of TERT and telomerase activity is increased in atherosclerotic plaques. However, the role of TERT dysregulation during atherosclerosis formation remains unknown.
The work herein first identified a multi-tiered regulation of TERT expression in smooth muscle cells (SMC) through histone deacetylase (HDAC) inhibition. HDAC inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Furthermore, during vascular remodeling in vivo, TERT protein expression in the neointima is prevented by HDAC inhibition. These data illustrate a differential regulation of TERT transcription and protein stability by HDAC inhibition. TERT is highly expressed in replicating SMC of atherosclerotic and neointimal lesions. Using a model of guidewire-induced arterial injury, neointima formation was reduced in TERT-deficient mice. Studies in SMC isolated from TERT-deficient and TERT overexpressing mice with normal telomere length established that TERT is necessary and sufficient for cell proliferation. TERT deficiency did not induce a senescent phenotype but resulted in G1 arrest albeit hyperphosphorylation of the retinoblastoma protein. This proliferative arrest was associated with stable silencing of the E2F1-dependent S-phase gene expression program which could not be reversed by ectopic overexpression of E2F1. Chromatin immunoprecipitation and accessibility assays revealed that TERT was recruited to E2F1 target sites to increase chromatin accessibility for E2F1 by facilitating the acquisition of permissive histone modifications. These data indicate a mitogenic effect of TERT on SMC growth and neointima formation through epigenetic regulation of proliferative gene expression. Furthermore, TERT expression is induced in activated macrophages during experimental and human atherosclerosis formation. To investigate the role for TERT in lesional macrophages and the subsequent effect on atherosclerosis formation, TERT-deficient mice were crossbred with LDL-receptor-deficient (LDLr-/-) mice to generate first generation G1TERT-/-LDLr-/- offsprings, which were then further intercrossed to obtain third generation G3TERT-/-LDLr-/- mice. G1TERT-/-LDLr-/- mice revealed no telomere shortening while severe telomere attrition was evident in G3TERT-/-LDLr-/- mice. When fed an atherogenic diet, G1TERT-/-LDLr-/- and G3TERT-/-LDLr-/- mice were both protected from atherosclerosis formation compared to their wild-type controls, indicating that genetic TERT-deletion prevents atherosclerosis, and formation of the disease is not affected by telomere attrition. Similarly, atherosclerosis development was decreased in chimeric LDLr-/- mice with TERT deletion in hematopoietic stem cells after bone marrow transplantation. TERT deficiency reduced macrophage accumulation in atherosclerotic lesions and altered chemokine expression, including CXC1/2/3, CCL3, CCL5, CCL21, CCR7, IL-6, and IL-1α. In isolated macrophages, gene ontology (GO) enrichment analysis of silenced inflammatory genes indicated that TERT positively regulates signal transducer and activator of transcription (STAT) cascade, which was confirmed by the decreased tyrosine phosphorylation of STAT3 protein resulting from TERT deletion. These findings indicate genetic TERT deficiency decreases atherosclerosis formation by silencing inflammatory chemokine transcription through inactivation of the STAT3 signaling pathway in activated macrophages.
In conclusion, the dysregulation of TERT expression within atherosclerotic plaques plays a causative role for vascular remodeling, including injury-induced neointima formation and hypercholesterolemia-induced atherosclerosis, through inducing SMC proliferation and a pro-inflammatory phenotype in infiltrating macrophages. These findings unveil a mechanism of TERT exacerbating the pathological vascular remodeling, which may provide a novel therapeutic target to combating vascular diseases.
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Davenport, Carolyn Marie Connor. "Multispectral fluorescence imaging of atherosclerosis." Diss., The University of Arizona, 1992. http://hdl.handle.net/10150/186077.
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Multispectral fluorescence imaging is a new diagnostic technique with the potential to provide improved detection and classification of atherosclerotic disease. This technique involves imaging the fluorescence response of a tissue region through a tunable band-pass filtering device. The result is a set of images in which each individual image is composed of the fluorescence emission within a specified band of wavelengths. Multispectral imaging combined with angioscopic technology allows direct access to important spectral information and spatial attributes providing the potential for more informed clinical decisions about which, if any, treatment modality is indicated. In this dissertation, the system requirements for an angioscopic system with multispectral imaging capability are identified. This analysis includes a description of the necessary optical components and their characteristics as well as the experimental determination of spectral radiance values for the fluorescence response of human aorta specimens and the estimation of anticipated signal-to-noise ratios for the spectral images. Other issues investigated include the number of spectral images required to provide good classification potential and the best normalization method to be utilized. Finally, the potential utility of the information contained within a multispectral data set is demonstrated. Two methods of utilizing the multispectral data are presented. The first method involves generating a ratio-image from the ratio of the intensities of two spectrally filtered images. The second method consists of using histologically verified training data to train a projector and then applying that projector to a set of spectral images. The result (a weighted sum of the spectral images) provides improved contrast between normal and diseased tissue, and is called an optimized-contrast image. White-light images (generated using an incandescent light source), total-fluorescence images (the fluorescence response without spectral filtering), ratio-images, and optimized contrast images are compared. The results indicate that angioscopic fluorescence imaging appears to be a feasible and potentially useful technique in terms of providing improved detection of atherosclerotic disease. This technique warrants further investigation to further define the system requirements and to evaluate its clinical usefulness including the collection of a more extensive data set and the development of a prototype system.
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Zhu, Chengcheng. "High resolution black blood magnetic resonance imaging of atherosclerotic plaque." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648792.
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Persson, Jerker. "Ultrasound and atherosclerosis evaluation of methods, risk factors and intervention /." Malmö : Lund : Malmö University Hospital ; Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/68945104.html.
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Dunn, Erin Kristine. "Endothelial nuclear hormone receptors in atherosclerosis." Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3402333.
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Thesis (Ph. D.)--University of California, San Diego, 2010.<br>Title from first page of PDF file (viewed May 19, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (leaves 50-56).
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Hägg, Sara. "Gene Expression Profiling of Human Atherosclerosis." Doctoral thesis, Linköpings universitet, Biologiska Beräkningar, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-52085.
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Atherosclerosis is a progressive inflammatory disease that causes lipid accumulation in the arterial wall, leading to the formation of plaques. The clinical manifestations of plaque rupture—stroke and myocardial infarction—are increasing worldwide and pose an enormous economic burden for society. Atherosclerosis development reflects a complex interaction between environmental exposures and genetic predisposition. To understand this complexity, we hypothesized that a top-down approach—one in which all molecular activities that drive atherosclerosis are examined simultaneously—is necessary to highlight those that are clinically relevant. To this end, we performed whole-genome expression profiling in multiple tissues isolated from patients with coronary artery disease (CAD). In the Stockholm Atherosclerosis Gene Expression (STAGE) study, biopsies of five tissues (arterial wall with and without atherosclerotic lesions, liver, skeletal muscle and visceral fat) were isolated from 124 CAD patients undergoing coronary artery bypass grafting surgery (CABG) at the Karolinska University Hospital, Solna and carotid lesions from 39 patients undergoing carotid artery surgery at Stockholm Söder Hospital. Detailed clinical characteristics of these patients were assembled together with a total of 303 global gene expression profiles obtained with the Affymetrix GeneChip platform. In paper 1, a two-way clustering analysis of the data identified 60 tissue clusters of functionally related genes. One cluster, partly present in both visceral fat and atherosclerotic lesions, related to atherosclerosis severity as judged by coronary angiograms. Many of the genes in that cluster were also present in a carotid lesion cluster relating to intima-media thickness (IMT) in the carotid patients. The union of all three clusters relating to extent of atherosclerosis—referred to as the “A-module”—was overrepresented with genes belonging to the transendothelial migration of leukocyte (TEML) pathway. The transcription co-factor, Lim domain binding 2 (LDB2), was identified as putative regulator of the A-module and TEML pathway in validation studies including Ldb2-/- mice. In paper 2, we investigated the increased incidence of postoperative complications in CABG patients with diabetes. Using the STAGE compendium, we identified an anti-inflammatory marker, dual-specificity phosphatase 1 (DUSP1), as a novel preoperative blood marker of risk for a prolonged hospital stay after CABG. In paper 3, plaque age was determined with C14-dating in the carotid patients. Interestingly, the strongest correlation with plaque age was not the age of the patients or IMT. Rather, the strongest correlations were with plasma insulin levels and inflammatory gene expression. Taken together, the findings in this thesis show that a top-down approach using multi-tissue gene expression profiling in CAD and C14-dating of plaques can contribute to a better understanding of the molecular processes underlying atherosclerosis development and to the identification of clinically useful biomarkers.
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Neuger, Lucyna. "Aspects on lipoprotein lipase and atherosclerosis." Doctoral thesis, Umeå : Univ, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-564.
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Wuttge, Dirk Marcus. "Cellular immunity and inflammation in atherosclerosis /." Stockholm : Karolinska Univ. Press, 2001. http://diss.kib.ki.se/2001/91-7349-051-2/.
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Sluimer, Judith Christina. "Hypoxia, HIF and angiogenesis in atherosclerosis." Maastricht : Maastricht : Universitaire pers Maastricht ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=10707.
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Leeuw, Karina de. "Premature atherosclerosis in systemic autoimmune diseases." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2008. http://irs.ub.rug.nl/ppn/.
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Rafatian, Naimeh. "Role of Cathepsin G in Atherosclerosis." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23641.
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Angiotensin II (Ang II) is an important modulator for development of atherosclerosis from early stage foam cell formation to advanced stage plaque rupture. Recently, the importance of locally generated Ang II, especially in macrophages, has become more evident. Generation of Ang II by several enzymes other than ACE and renin has been shown mainly in vitro. Cathepsin G is one these enzymes which is expressed in neutrophils and macrophages. Macrophages are one of the primary and crucial cells in atherosclerotic lesions which become lipid-laden foam cells through lipoprotein uptake. We hypothesized that activation of nuclear factors in foam cells increases Ang II by modulation of the renin angiotensin system (RAS) genes and cathepsin G. We also hypothesized that cathepsin G, through its Ang II generating activity and its other catalytic functions, promotes atherosclerosis.
The present study assessed the Ang I and II levels and expression of the RAS genes in THP-1 cells, a human acute monocytic leukemia cell line, and in peritoneal and bone marrow-derived macrophages after exposure to acetylated LDL (ac-LDL). I also evaluated how RAS blockade would affect foam cell formation in THP-1 cells. In parallel, I assessed the role of cathepsin G in Ang II generation and in the progression of atherosclerosis in cathepsin G heterozygous knockout mice on an Apoe-/- background (Ctsg+/-Apoe-/- mice).
Ac-LDL treatment increased Ang I and Ang II levels in cell lysates and media from THP-1 cells but not in peritoneal or bone marrow-derived macrophages from wild type C57BL/6 mice. In ac-LDL-treated THP-1 cells, ACE and cathepsin G mRNA levels and activities were elevated. Angiotensinogen mRNA is increased but not the angiotensinogen protein concentration. Renin mRNA level and activity were not altered by ac-LDL treatment. Blocking RAS by an AT1 receptor blocker, ACE inhibitors or a renin inhibitor decreased cholesteryl ester content of THP-1 cells after exposure to ac-LDL. To confirm that the Ang II effect on foam cell formation was not unique to ac-LDL, we treated the THP-1 macrophages with a renin inhibitor or an AT1 receptor inhibitor after exposure to oxidized LDL (ox-LDL). RAS blockade in ox-LDL-treated cells also abolished cholesteryl ester formation. To see how Ang II plays a role in foam cell formation we assessed the effect of RAS inhibitors on SR-A, the principal receptor for mediating ac-LDL entry into the cells and on acyl-CoA:cholesterol acyl transferase (ACAT-1), the enzyme responsible for intracellular cholesterol esterification. RAS blockade in both ac-LDL- and ox-LDL-treated cells decreased SR-A and ACAT-1 protein levels.
Cathepsin G partial deficiency on an Apoe-/- background did not change Ang II levels in peritoneal or bone marrow-derived macrophage cell lysates or media. This deficiency also did not affect immunoreactive angiotensin peptide levels in atherosclerotic lesions. After 8 weeks on a high fat diet Ctsg+/-Apoe-/- mice were similar to Ctsg+/+Apoe-/- mice in terms of lesion size and serum cholesterol levels but the Ctsg+/+Apoe-/- mice had more advanced lesions with more collagen and smooth muscle cells and fewer macrophages. Moreover, Ctsg+/+Apoe-/- mice had more apoptotic cells than their Ctsg+/-Apoe-/- littermates.
Overall, our findings indicate that Ang II is increased in foam cells and this endogenous Ang II is involved in cholesteryl ester formation, possibly by regulating the levels of ACAT-1 and SR-A. We did not find any role for cathepsin G in generation of Ang II in mice but cathepsin G does, nevertheless, promote the progression of atherosclerotic lesions to a more advanced stage.
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Pierides, C. "Immune responses against atherosclerosis-related antigens." Thesis, University of Surrey, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529425.
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Milioti, Natalia. "Immunomodulation of atherosclerosis using dendritic cells." Thesis, University of Surrey, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608344.
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Inflammation plays a crucial role in atherosclerotic plaque generation/progression. Dendritic cells (DCs). cellular immune-response components linking innate and adaptive immune systems, have been found in atherosclerotic plaques. In this study, Des were examined as a possible therapeutic tool to modulate the inflammatory immune response underlying plaque formation. Apolipoprotein (apo) B-100 derived antigens are believed to modulate humoral immune responses to achieve atheroprotection, but their role in cellular immunity remains unclear. Therefore, one objective was to characterise the immunomodulatory effect of apoB-100-derived peptides (P2, P45, P210) on immature DCs (iDCs) and naive T lymphocytes ill vitro. iDCs were generated from bone-marrow progenitor-cells of male apoE-'- mice. Peptide up-take and processing was studied by confocal microscopy after 6h, 2411 and 48h. Peptide P45 was found in the endolysosomal compartments, co-localising with MHC-I and :MHC-II antigen-presenting complexes. The phenotypic and differentiation characteristics of P2, P45 and P21O-Joaded DCs were studied by flow cytometry, and cytokine and matrix metalloproleinase production by PCR/ELISA after 48h. Proliferation and differentiation of T lymphocytes driven by peptide-loaded DCs was also studied. Peptide-loaded DCs displayed a tolerogenie phenotype similar to that of unloaded, iDCs, and inhibited CD4+ proliferation induced by mature DCs when co-cultured. My results suggest that the protective effect of the peptides could be mediated by DCs presenting them to T cells. A second objective was to examine the effect of vaccination with tolerogenic DCs (toIDCs), generated in vitro through incubation with IL-10 and TGF-β for 6 days, on atherosclerotic progression in apoE-/- mice. This showed that immunisation with tolDCs increased the number of CD8+CD25'FoxP3+ T regulatory cells as well as secretion of IL-l0 within the spleen of immunised mice. IL- l0 levels were also elevated in the serum, while cholesterol levels were reduced, although plaque size remained unchanged. These results provide new insights for treatment and prevention of atherosclerosis through vaccination.
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Tai, Daven C. H. "STAT6 and STAT4 in murine atherosclerosis." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/45653.
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Atherosclerosis is a chronic inflammatory condition and the major underlying cause of heart attacks and strokes. Since the immune system is paramount in all stages of atherosclerosis, modulating the immune response is an attractive therapeutic strategy for atherosclerotic disease. Signal transducers and activators of transcription (STAT) 6 and STAT4 are essential orchestrators of the anti-inflammatory Th2 response and the pro-inflammatory Th1 response, respectively. Using bone marrow transplantation to deplete STAT6 and STAT4 expression in specific immune compartments in low density lipoprotein receptor knockout (Ldlr-/-) mice, we investigated the validity of modulating the immune response through STAT6 and STAT4 as a prospective treatment strategy for atherosclerosis. We found that myeloid-specific STAT6 depletion did not significantly impact atherosclerotic lesion area or stability in Ldlr-/- mice fed an atherogenic diet for 8 or 14 weeks. In addition, hematopoiesis in the myeloid and lymphoid lineages was not significantly affected by the absence of myeloid STAT6. In contrast, total hematopoietic system STAT4 depletion profoundly exacerbated atherosclerotic lesion area and vulnerability in Ldlr-/- mice following 8 weeks of atherogenic diet. Hematopoietic perturbations in mice transplanted with STAT4-deficient bone marrow are highly reminiscent of interferon (IFN)-gamma-dependent effects on immune cell development in interleukin-12-treated mice, suggesting that IFN-gamma levels may be elevated in response to hypercholesterolemia in the absence of STAT4. Myeloid-specific STAT4-deficient mice also developed larger atherosclerotic lesions in the aortic root, providing evidence that even partial STAT4 insufficiency can potentially accelerate atherosclerosis. This thesis provides novel insights into the functions of STAT6 and STAT4 in atherosclerosis.
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Satterthwaite, Gemma. "Discovery of diagnostic markers for atherosclerosis." Thesis, University of Sheffield, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274961.
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Grahame-Clarke, Christine Naomi Ellinor. "The role of herpesviruses in atherosclerosis." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252101.
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Overed-Sayer, Catherine Lucy. "Inflammation in atherosclerosis : modulation by tamoxifen." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611124.
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Raftis, Jennifer. "Nanoparticles and atherosclerosis : resolving the paradox." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8796.
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Air pollution is increasingly recognised as an important and modifiable risk factor for cardiovascular disease. Exposure is associated with a range of adverse cardiovascular events including hospital admissions with angina and myocardial infarction, and with cardiovascular death. The main arbiter of these adverse health effects appears to be combustion-derived nanoparticles that incorporate reactive organic and transition metal components. Through the induction of cellular oxidative stress and pro-inflammatory pathways, these nanoparticles exert detrimental effects on platelets, vasculature and myocardium, and can augment the development and progression of atherosclerosis. Over the last 10 years there has been remarkable progress in the development of targeted engineered nanoparticles as contrast agents to enhance cellular and molecular imaging. Ultra-small paramagnetic iron oxide (USPIO) nanoparticles (<100 nm) produce disruptions in the magnetic field of magnetic resonance imaging (MRI) scanners, and a decrease in image intensity in areas where the particles accumulate. USPIO particles are phagocytosed by cells of the monocyte-macrophage system throughout the body including within atheromatous plaques. USPIOs have regulatory approval in the United Kingdom for imaging lymph nodes in breast and prostate cancer as well as FDA approval for parenteral iron-replacement therapy in chronic kidney disease. There is great interest in developing USPIO and other nanoparticle contrast agents for imaging atherosclerosis. The delivery of engineered nanoparticles (ENPs) directly into the bloodstream to provide enhanced imaging of the unstable atheromatous plaque may assist in the diagnosis of plaque rupture and may ultimately permit targeted delivery of therapies directly to the site of vascular injury. However, these particles once blood-borne may alter monocyte-macrophage function and activate circulating platelets with adverse effects on clinical outcomes. Previously it has been shown that inhalation of combustion-derived nanoparticles results in increases in platelet-monocyte aggregation and thrombus formation in healthy volunteers. These combustion derived nanoparticles share structural similarities with engineered nanoparticles designed for intravascular infusion. This raises an obvious paradoxical question: can engineered nanoparticles designed for medical use mediate similar effects to combustion derived nanoparticles in susceptible populations? My thesis addresses this question and describes a series of complimentary experimental and clinical studies to investigate the effects of engineered nanoparticles on platelet function and thrombogenesis using commercial and clinically available nanoparticles. I found that cationic nanoparticles caused platelet activation and aggregation in vitro, whereas, anionic nanoparticles caused inflammation and up-regulated adhesion molecule ICAM-1 in monocyte derived macrophages indicating that nanoparticles have different toxicological properties in different biological conditions. Using an ex vivo model of thrombus formation, the Badimon chamber, I observed that USPIO nanoparticles added to flowing native whole blood in an extra-corporeal circuit increased platelet rich thrombus formation under high shear conditions compared to saline control in healthy volunteers. These studies were repeated in patients with abdominal aortic aneurysms who received intra-venous systemic infusions of USPIO to enhance MRI imaging. I demonstrated up-regulation in markers of platelet activation and more platelet rich thrombus formation in the Badimon chamber one hour following systemic delivery of USPIO. In summary I have demonstrated that medical nanoparticles influence platelet activation in patients with cardiovascular disease and have pro-thrombotic effects in an ex-vivo model of in both healthy persons and susceptible patients. In light of this data and to ensure the safe future development of engineered nanoparticles for medical use platelet activation assays and follow-up monitoring of patients should be considered routine in both the developmental and clinical stages of engineered nanoparticle use.
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Yu, Emma Pei Kuen. "Mitochondrial DNA damage, dysfunction and atherosclerosis." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648537.
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Seibel, Yasmine. "The Role of Serotonin in Atherosclerosis." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/21818.
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Atherosklerose ist eine verbreitete Krankheit deren Pathogenese unzureichend erforscht ist. Bekannt ist jedoch, dass externe und interne Faktoren eine Rolle spielen. Die zugrunde liegenden Prozesse müssen genauer untersucht werden, um neue Therapieansätze zu entwickeln.
Als Allroundtalent könnte Serotonin (5-HT) ein Kandidat sein, der eine entscheidende Rolle bei der atherosklerotischen Pathogenese spielt. Ob und wie dieses Hormon die Bildung atherosklerotischer Plaques, Makrophageninvasion, Verkalkung und Fibrose beeinflusst, war Gegenstand dieser Studie.
Die vorliegende Studie ist die erste ihrer Art, die den neuartigen Ansatz von transgenen Doppel-Knockout-Mäusen verwendet, denen das Apolipoprotein E (ApoE) fehlt und, die das Schlüsselenzym für die periphere 5-HT-Synthese, Tryptophanhydroxylase 1 (Tph1), oder den primären 5-HT-Transporter (SERT) nicht bilden. Physiologie, Stoffwechselparameter und atherogene Prozesse wurden in ApoE/Tph1-/- und ApoE/Sert-/- Tieren mithilfe eines breiten Methodenspektrums untersucht und resultierten in einem umfassenden Überblick über die Wirkungsweisen von 5-HT auf Atherosklerose.
Die 5-HT-Rezeptorverteilung ist unterschiedlich in Gefäßen von verschiedenen Mauslinien und in denen von Tieren mit Tph1-Defizienz, die in diesen Linien erzeugt wurden. Ferner weisen ApoE/Tph1-/- und ApoE/Sert-/- verschiedene Phänotypen auf: Tph1-Defizienz führt zu verminderter Zunahme des Körpergewichts, niedrigerem Plasmacholesterin und Leberparametern und erhöhtem Lebergewicht. Sert-Defizienz bedingt erhöhten Blutzucker, Plasmacholesterin und die Ausbildung größerer Plaques, sowie vermehrte Kollagenakkumulation. Die Langzeitgabe einer Western-Diät zeigte, dass Tph1-Defizienz schützende Wirkung auf den Lipidstoffwechsel hat, ein klarer Effekt auf die Atherogenese konnte nicht ermittelt werden.
Zusammenfassend hebt diese Studie die komplexen Beziehungen vieler Faktoren während der Krankheit hervor. 5-HT spielt bei vielen dieser Faktoren eine Rolle, scheint jedoch nur eine schwache aber protektive Wirkung auf Atherogenese selbst zu haben.<br>Atherosclerosis is a common disease and its pathogenesis is only poorly understood. It’s known that external and internal factors play a role, but the exact processes need to be investigated more intensively to develop novel therapy approaches.
As an all-round talent, serotonin (5-HT) might be a promising candidate to play a crucial role in atherosclerosis. If and how 5-HT affects atherosclerotic plaque formation, macrophage invasion, calcification and fibrosis was focus of this study.
This study is the first of its kind using the novel approach of transgenic double knockout mice lacking the apolipoprotein E (ApoE, atherosclerosis model) and either the key enzyme in peripheral 5-HT synthesis, tryptophan hydroxylase 1 (Tph1) or the major 5-HT transporter, SERT. Physiology, metabolic parameters and atherogenic processes in ApoE/Tph1-/- and ApoE/Sert-/- animals were examined using a broad spectrum of methods and resulted in an extensive overview of how 5-HT might influence the pathogenesis of atherosclerosis.
Most striking results of this study:
5-HT receptor distribution is altered in vessels of different background strains, and also in Tph1 deficient animals generated in these strains. Further, the examination of ApoE/Tph1-/- and ApoE/Sert-/- mice elucidated that both double knockouts exhibit different phenotypes: While Tph1 deficiency resulted in decreased bodyweight, plasma cholesterol and liver parameters and increased liver weight, Sert deficiency caused increases in blood glucose, plasma cholesterol, plaque size and collagen in plaques. Long term Western Diet application confirmed that Tph1 deficiency decreases weight gain and has protective effects on lipid metabolism, but a clear effect on atherogenesis could not be reported.
Concluding, this study highlights the complex relationship between many factors acting on atherosclerotic pathogenesis. 5-HT plays a role in many of those factors, but seems to have only minor but protective effects on atherogenesis itself.
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Scalzi, Lisabeth Victoria. "Subclinical Atherosclerosis in Systemic Lupus Erythematosus." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1212695307.
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