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Journal articles on the topic 'Hypertrophy'
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1
Maron, Barry J., and Carolyn Y. Ho. "Hypertrophic Cardiomyopathy Without Hypertrophy." JACC: Cardiovascular Imaging 2, no. 1 (January 2009): 65–68. http://dx.doi.org/10.1016/j.jcmg.2008.09.008.
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Strøm, Claes C., Mogens Kruhøffer, Steen Knudsen, Frank Stensgaard-Hansen, Thomas E. N. Jonassen, Torben F. Ørntoft, Stig Haunsø, and Søren P. Sheikh. "Identification of a Core Set of Genes That Signifies Pathways Underlying Cardiac Hypertrophy." Comparative and Functional Genomics 5, no. 6-7 (2004): 459–70. http://dx.doi.org/10.1002/cfg.428.
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Although the molecular signals underlying cardiac hypertrophy have been the subject of intense investigation, the extent of common and distinct gene regulation between different forms of cardiac hypertrophy remains unclear. We hypothesized that a general and comparative analysis of hypertrophic gene expression, using microarray technology in multiple models of cardiac hypertrophy, including aortic banding, myocardial infarction, an arteriovenous shunt and pharmacologically induced hypertrophy, would uncover networks of conserved hypertrophy-specific genes and identify novel genes involved in hypertrophic signalling. From gene expression analyses (8740 probe sets,n= 46) of rat ventricular RNA, we identified a core set of 139 genes with consistent differential expression in all hypertrophy models as compared to their controls, including 78 genes not previously associated with hypertrophy and 61 genes whose altered expression had previously been reported. We identified a single common gene program underlying hypertrophic remodelling, regardless of how the hypertrophy was induced. These genes constitute the molecular basis for the existence of one main form of cardiac hypertrophy and may be useful for prediction of a common therapeutic approach. Supplementary material for this article can be found at: http://www.interscience.wiley.com/jpages/1531-6912/suppmat
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Li, Wei-ming, Yi-fan Zhao, Guo-fu Zhu, Wen-hui Peng, Meng-yun Zhu, Xue-jing Yu, Wei Chen, Da-chun Xu, and Ya-wei Xu. "Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload." Clinical Science 131, no. 2 (December 23, 2016): 141–54. http://dx.doi.org/10.1042/cs20160664.
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Pathological cardiac hypertrophy is an independent risk factor of heart failure. However, we still lack effective methods to reverse cardiac hypertrophy. DUSP12 is a member of the dual specific phosphatase (DUSP) family, which is characterized by its DUSP activity to dephosphorylate both tyrosine and serine/threonine residues on one substrate. Some DUSPs have been identified as being involved in the regulation of cardiac hypertrophy. However, the role of DUSP12 during pathological cardiac hypertrophy is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in hypertrophic hearts and cardiomyocytes. Using a genetic loss-of-function murine model, we demonstrated that DUSP12 deficiency apparently aggravated pressure overload-induced cardiac hypertrophy and fibrosis as well as impaired cardiac function, whereas cardiac-specific overexpression of DUPS12 was capable of reversing this hypertrophic and fibrotic phenotype and improving contractile function. Furthermore, we demonstrated that JNK1/2 activity but neither ERK1/2 nor p38 activity was increased in the DUSP12 deficient group and decreased in the DUSP12 overexpression group both in vitro and in vivo under hypertrophic stress conditions. Pharmacological inhibition of JNK1/2 activity (SP600125) is capable of reversing the hypertrophic phenotype in DUSP12 knockout (KO) mice. DUSP12 protects against pathological cardiac hypertrophy and related pathologies. This regulatory role of DUSP12 is primarily through c-Jun N-terminal kinase (JNK) inhibition. DUSP12 could be a promising therapeutic target of pathological cardiac hypertrophy. DUSP12 is down-regulated in hypertrophic hearts. An absence of DUSP12 aggravated cardiac hypertrophy, whereas cardiomyocyte-specific DUSP12 overexpression can alleviate this hypertrophic phenotype with improved cardiac function. Further study demonstrated that DUSP12 inhibited JNK activity to attenuate pathological cardiac hypertrophy.
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Lu, Peilei, Danyu Zhang, Fan Ding, Jialu Ma, Yang K. Xiang, and Meimi Zhao. "Silencing of circCacna1c Inhibits ISO-Induced Cardiac Hypertrophy through miR-29b-2-5p/NFATc1 Axis." Cells 12, no. 12 (June 19, 2023): 1667. http://dx.doi.org/10.3390/cells12121667.
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Pathological cardiac hypertrophy is one of the notable causes of heart failure. Circular RNAs (circRNAs) have been studied in association with cardiac hypertrophy; however, the mechanisms by which circRNAs regulate cardiac hypertrophy remain unclear. In this study, we identified a new circRNA, named circCacna1c, in cardiac hypertrophy. Adult male C57BL/6 mice and H9c2 cells were treated with isoprenaline hydrochloride (ISO) to establish a hypertrophy model. We found that circCacna1c was upregulated in ISO-induced hypertrophic heart tissue and H9c2 cells. Western blot and quantitative real-time polymerase chain reaction showed that silencing circCacna1c inhibited hypertrophic gene expression in ISO-induced H9c2 cells. Mechanistically, circCacna1c competitively bound to miR-29b-2-5p in a dual-luciferase reporter assay, which was downregulated in ISO-induced hypertrophic heart tissue and H9c2 cells. MiR-29b-2-5p inhibited the nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) to control hypertrophic gene expression. After silencing circCacna1c, the expression of miR-29b-2-5p increased, which reduced hypertrophic gene expression by inhibiting NFATc1 expression. Together, these experiments indicate that circCacna1c promotes ISO-induced pathological hypertrophy through the miR-29b-2-5p/NFATc1 axis.
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Savchenko, M. I., YU R. Kovalev, and A. P. Kuchinskiy. "HYPERTROPHIC CARDIOMYOPATHY: FIBROSIS OR HYPERTROPHY." "Arterial’naya Gipertenziya" ("Arterial Hypertension") 19, no. 2 (April 28, 2013): 148–55. http://dx.doi.org/10.18705/1607-419x-2013-19-2-148-155.
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Objective.Despite the high frequency — 0,2 % (1:500) population, hypertrophic cardiomyopathy (HCM) is still considered one of the most mysterious and misunderstood diseases of myocardium. Insidious pathology has neither specific anatomical and morphological, nor clinical features which makes it a delayed-action bomb: nobody is capable to predict when and what clinical symptoms develop. The clinical phenotype of HCM varies from latent course when the symptoms are absent till rapid progress of heart failure syndrome and sudden cardiac death due to severe arrhythmia. The review covers modern view on genetics, morphology and pathogenesis of HCM.
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Abdelbaki, Mourad, A. Boureghda, and N. Hanifi. "Comparative Research Between Sportsman's Heart and Hypertrophic Cardiomyopathy." International Journal of Innovative Research in Medical Science 9, no. 01 (January 10, 2024): 24–27. http://dx.doi.org/10.23958/ijirms/vol09-i01/1802.
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Physiological left ventricular hypertrophy is the result of the left ventricle having to function harder due to intense physical exercise. After exercise is stopped, this modest and reversible hypertrophy persists. Studying these structural alterations is now feasible because to cardiac echodoppler. Distinguishing this adaptive hypertrophy from the pathogenic hypertrophic cardiomyopathy might be challenging at times. We examined 212 athletes who competed and a group of hypertrophic cardiomyopathy patients who had asymmetric septal hypertrophy that was confirmed. The findings demonstrated that there is a boundary between pathological and normal hypertrophy. This zone contained four athletes, one of whom had hypertrophic cardiomyopathy. Numerous variables led to the diagnosis, including the patient's history, electrical anomalies, septal thickness, and a diastolic diameter of less than 45 mm. Deconditioning further supported the diagnosis.
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Morita, Kozo, Takeshi Miyamoto, Nobuyuki Fujita, Yoshiaki Kubota, Keisuke Ito, Keiyo Takubo, Kana Miyamoto, et al. "Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification." Journal of Experimental Medicine 204, no. 7 (June 18, 2007): 1613–23. http://dx.doi.org/10.1084/jem.20062525.
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Chondrocyte hypertrophy during endochondral ossification is a well-controlled process in which proliferating chondrocytes stop proliferating and differentiate into hypertrophic chondrocytes, which then undergo apoptosis. Chondrocyte hypertrophy induces angiogenesis and mineralization. This step is crucial for the longitudinal growth and development of long bones, but what triggers the process is unknown. Reactive oxygen species (ROS) have been implicated in cellular damage; however, the physiological role of ROS in chondrogenesis is not well characterized. We demonstrate that increasing ROS levels induce chondrocyte hypertrophy. Elevated ROS levels are detected in hypertrophic chondrocytes. In vivo and in vitro treatment with N-acetyl cysteine, which enhances endogenous antioxidant levels and protects cells from oxidative stress, inhibits chondrocyte hypertrophy. In ataxia telangiectasia mutated (Atm)–deficient (Atm−/−) mice, ROS levels were elevated in chondrocytes of growth plates, accompanied by a proliferation defect and stimulation of chondrocyte hypertrophy. Decreased proliferation and excessive hypertrophy in Atm−/− mice were also rescued by antioxidant treatment. These findings indicate that ROS levels regulate inhibition of proliferation and modulate initiation of the hypertrophic changes in chondrocytes.
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Gu, Wei, Yutong Cheng, Su Wang, Tao Sun, and Zhizhong Li. "PHD Finger Protein 19 Promotes Cardiac Hypertrophy via Epigenetically Regulating SIRT2." Cardiovascular Toxicology 21, no. 6 (February 21, 2021): 451–61. http://dx.doi.org/10.1007/s12012-021-09639-0.
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AbstractEpigenetic regulations essentially participate in the development of cardiomyocyte hypertrophy. PHD finger protein 19 (PHF19) is a polycomb protein that controls H3K36me3 and H3K27me3. However, the roles of PHF19 in cardiac hypertrophy remain unknown. Here in this work, we observed that PHF19 promoted cardiac hypertrophy via epigenetically targeting SIRT2. In angiotensin II (Ang II)-induced cardiomyocyte hypertrophy, adenovirus-mediated knockdown of Phf19 reduced the increase in cardiomyocyte size, repressed the expression of hypertrophic marker genes Anp and Bnp, as well as inhibited protein synthesis. By contrast, Phf19 overexpression promoted Ang II-induced cardiomyocyte hypertrophy in vitro. We also knocked down Phf19 expression in mouse hearts in vivo. The results demonstrated that Phf19 knockdown reduced Ang II-induced decline in cardiac fraction shortening and ejection fraction. Phf19 knockdown also inhibited Ang II-mediated increase in heart weight, reduced cardiomyocyte size, and repressed the expression of hypertrophic marker genes in mouse hearts. Further mechanism studies showed that PHF19 suppressed the expression of SIRT2, which contributed to the function of PHF19 during cardiomyocyte hypertrophy. PHF19 bound the promoter of SIRT2 and regulated the balance between H3K27me3 and H3K36me3 to repress the expression of SIRT2 in vitro and in vivo. In human hypertrophic hearts, the overexpression of PHF19 and downregulation of SIRT2 were observed. Of importance, PHF19 expression was positively correlated with hypertrophic marker genes ANP and BNP but negatively correlated with SIRT2 in human hypertrophic hearts. Therefore, our findings demonstrated that PHF19 promoted the development of cardiac hypertrophy via epigenetically regulating SIRT2.
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Ignatenko, G. I., G. G. Taradin, and T. E. Kugler. "Specifics of Left Ventricular Hypertrophy and Characteristic of Phenotypic Variants in Patients with Hypertrophic Cardiomyopathy." Russian Archives of Internal Medicine 13, no. 4 (August 16, 2023): 282–93. http://dx.doi.org/10.20514/2226-6704-2023-13-4-282-293.
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Hypertrophic cardiomyopathy is characterized by genetic and phenotypic heterogeneity which manifests in different variants of localization and extent of myocardial hypertrophy.Aim: to evaluate specifics of left ventricular hypertrophy, the prevalence and characteristics of clinical and instrumental features of phenotypic variants of hypertrophic cardiomyopathy.Materials and methods. The study includes 295 patients with hypertrophic cardiomyopathy aged 18 to 88 years (60.3±13.4 years), 183 men (62 %), and women 112 (38 %). The diagnosis of which was established by 2D echocardiography. The severity, localization and extent of myocardial hypertrophy, the maximum thickness of the hypertrophied segment, left ventricular myocardial mass, left ventricular myocardial mass index, the presence and severity of mid-ventricular and left ventricular outflow tract obstruction were evaluated. Depending on the predominant localization and extent of hypertrophy, patients were divided into 8 groups according to the recommendations for hypertrophic cardiomyopathy of the Ministry of Health of the Russian Federation. The analysis and comparison of the obtained results are carried out.Results. The average duration of the disease is 10.5±7.52 years. The mean values of the body mass index in patients — 28.2±2.82 kg/m2. The phenotype with basal hypertrophy of the septum (n=130, 44.1 %), group 1 was most often noted. In 47 (15.9 %) patients, hypertrophy of the septum of “reverse curve” (2 group) was detected, in 41 (13.9 %) — “neutral septum” (3 group), in 36 (12.2 %) — symmetrical hypertrophy of the left ventricle (8 group), 11 (3.7 %) of patients had combined hypertrophy of the septum and other parts of the left or right ventricle (4 group) and the free left ventricular wall (7 group), in 10 (3.4 %) — middle ventricular hypertrophy of the left ventricle (6 group) and in 9 (3.1 %) — apical hypertrophy (5 group). The highest value of the maximum thickness of the myocardium was noted in patients of the 6th group 19.3 (1920.4 mm). Mid-ventricular obstruction was detected in group 6 (90 %), left ventricular outflow tract obstruction was more often registered in groups 4 and 8 (81.8 % and 77.8 %), and less often in group 5 (22.2 %) (p <0.01). In group 7, there were no cases of rest obstruction of left ventricular outflow tract. The maximum values of myocardial mass and left ventricular myocardial mass index were noted in group 8 — 402 (356-439) g and 195 (173218) g/m2, respectively (p <0.01).Conclusion. Echocardiography is an informative tool for assessing the presence, severity myocardial hypertrophy and determination of the phenotypic variant of hypertrophic cardiomyopathy. Variants of septal hypertrophy are most commonly registered one, among which the most frequent is the phenotype of basal septal hypertrophy. Each phenotype of hypertrophic expression is characterized by its echocardiographic parameters.
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Villeneuve, C., A. Caudrillier, C. Ordener, N. Pizzinat, A. Parini, and J. Mialet-Perez. "Dose-dependent activation of distinct hypertrophic pathways by serotonin in cardiac cells." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 2 (August 2009): H821—H828. http://dx.doi.org/10.1152/ajpheart.00345.2009.
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There is substantial evidence supporting a hypertrophic action of serotonin [5-hydroxytryptamine (5-HT)] in cardiomyocytes. However, little is known about the mechanisms involved. We previously demonstrated that 5-HT-induced hypertrophy depends, in part, on the generation of reactive oxygen species by monoamine oxidase-A (MAO-A) (see Ref. 3 ). Cardiomyocytes express 5-HT2 receptors, which may also participate in hypertrophy. Here, we analyzed the respective contribution of 5-HT2 receptors and MAO-A in H9C2 cardiomyoblast hypertrophy. 5-HT induced a dose-dependent increase in [3H]leucine incorporation and stimulation of two markers of cardiac hypertrophy, ANF-luc and αSK-actin-luc reporter genes. Experiments using 1 μM 5-HT showed that hypertrophic response occurred independently from MAO-A. Using pharmacological inhibitors (M100907 and ketanserin), we identified a novel mechanism of action involving 5-HT2A receptors and requiring Ca2+/calcineurin/nuclear factor of activated T-cell activation. The activation of this hypertrophic pathway was fully prevented by 5-HT2A inhibitors and was unaffected by MAO inhibition. When 10 μM 5-HT was used, an additional hypertrophic response, prevented by the MAO inhibitors pargyline and RO 41-1049, was observed. Unlike the 5-HT2A-receptor-mediated H9C2 cell hypertrophy, MAO-A-dependent hypertrophic response required activation of extracellular-regulated kinases. In conclusion, our results show the existence of a dose-dependent shift of activation of distinct intracellular pathways involved in 5-HT-mediated hypertrophy of cardiac cells.
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Nosenko, N. M., D. V. Shchehlov, M. Yu Mamonova, and Ya E. Kudelskyi. "Left ventricular hypertrophy: differential diagnosis." Endovascular Neuroradiology 30, no. 4 (March 11, 2020): 49–58. http://dx.doi.org/10.26683/2304-9359-2019-4(30)-49-58.
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There are some imaging methods for the diagnosis of left ventricular hypertrophy. Such as echocardiography, computed tomography, magnetic resonance imaging. These methods help to identify changes at different stages, evaluate the prognosis, stratify the risk and differential diagnosis.The left ventricle hypertrophy is a condition that may be due to physiological adaptation due to overload. For example, in patients with arterial hypertension, in athletes, and so on. Left ventricle hypertrophy may also be associated with a change in the actual structure: for example, with hypertrophic cardiomyopathy.Signs of left ventricle hypertrophy by echocardiography are a very significant predictor of mortality in patients with arterial hypertension in the general population. The presence of left ventricle hypertrophy by echocardiography is a high cardiovascular risk for the patient.It is important to diagnose diseases with a high risk of sudden cardiac death on time. One of these diseases is hypertrophic cardiomyopathy. A clinical diagnosis of hypertrophic cardiomyopathy is impossible without visualization. Therefore, the European Association of Cardiovascular Imaging recommends a multimodal approach in examining patients with hypertrophic cardiomyopathy.Сomputed tomography, echocardiography, and magnetic resonance imaging are used to diagnose which patient’s hypertrophy is pathological or physiological. The choice of which method to use depends on the diagnostic task, and also on the specific advantages and disadvantages of the method. Different visualization methods should be considered complementary, not competing. It is also important to choose a particular imaging technique given its diagnostic value, availability, benefits, risks and costs.
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Olimovna, Oripova Ozoda. "CHARACTERISTICS OF PATHOMORPHOLOGICAL CHANGES IN HYPERTROPHIC CARDIOMYOPATHY." American Journal Of Biomedical Science & Pharmaceutical Innovation 4, no. 6 (June 1, 2024): 70–78. http://dx.doi.org/10.37547/ajbspi/volume04issue06-10.
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In hypertrophic cardiomyopathy, the walls of the ventricles of the heart continue with symmetric or asymmetric myocardial hypertrophy. Morphologically, in hypertrophic cardiomyopathy, fibrotic foci are detected based on the incorrect arrangement of myocardial muscle fibers, small coronary vessel syndrome, and myocardial hypertrophy.
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Raghunathan, Suchi, Ramesh K. Goyal, and Bhoomika M. Patel. "Selective inhibition of HDAC2 by magnesium valproate attenuates cardiac hypertrophy." Canadian Journal of Physiology and Pharmacology 95, no. 3 (March 2017): 260–67. http://dx.doi.org/10.1139/cjpp-2016-0542.
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The regulatory paradigm in cardiac hypertrophy involves alterations in gene expression that is mediated by chromatin remodeling. Various data suggest that class I and class II histone deacetylases (HDACs) play opposing roles in the regulation of hypertrophic pathways. To address this, we tested the effect of magnesium valproate (MgV), an HDAC inhibitor with 5 times more potency on class I HDACs. Cardiac hypertrophy was induced by partial abdominal aortic constriction in Wistar rats, and at the end of 6 weeks, we evaluated hypertrophic, hemodynamic, and oxidative stress parameters, and mitochondrial DNA concentration. Treatment with MgV prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress, and increased mitochondrial DNA concentration. MgV treatment also increased the survival rate of the animals as depicted by the Kaplan–Meier curve. Improvement in hypertrophy due to HDAC inhibition was further confirmed by HDAC mRNA expression studies, which revealed that MgV decreases expression of pro-hypertrophic HDAC (i.e., HDAC2) without altering the expression of anti-hypertrophic HDAC5. Selective class I HDAC inhibition is required for controlling cardiac hypertrophy. Newer HDAC inhibitors that are class I inhibitors and class II promoters can be designed to obtain “pan” or “dual” natural HDAC “regulators”.
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Riedl, Moritz, Christina Witzmann, Matthias Koch, Siegmund Lang, Maximilian Kerschbaum, Florian Baumann, Werner Krutsch, Denitsa Docheva, Volker Alt, and Christian Pfeifer. "Attenuation of Hypertrophy in Human MSCs via Treatment with a Retinoic Acid Receptor Inverse Agonist." International Journal of Molecular Sciences 21, no. 4 (February 20, 2020): 1444. http://dx.doi.org/10.3390/ijms21041444.
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In vitro chondrogenically differentiated mesenchymal stem cells (MSCs) have a tendency to undergo hypertrophy, mirroring the fate of transient “chondrocytes” in the growth plate. As hypertrophy would result in ossification, this fact limits their use in cartilage tissue engineering applications. During limb development, retinoic acid receptor (RAR) signaling exerts an important influence on cell fate of mesenchymal progenitors. While retinoids foster hypertrophy, suppression of RAR signaling seems to be required for chondrogenic differentiation. Therefore, we hypothesized that treatment of chondrogenically differentiating hMSCs with the RAR inverse agonist, BMS204,493 (further named BMS), would attenuate hypertrophy. We induced hypertrophy in chondrogenic precultured MSC pellets by the addition of bone morphogenetic protein 4. Direct activation of the RAR pathway by application of the physiological RAR agonist retinoic acid (RA) further enhanced the hypertrophic phenotype. However, BMS treatment reduced hypertrophic conversion in hMSCs, shown by decreased cell size, number of hypertrophic cells, and collagen type X deposition in histological analyses. BMS effects were dependent on the time point of application and strongest after early treatment during chondrogenic precultivation. The possibility of modifing hypertrophic cartilage via attenuation of RAR signaling by BMS could be helpful in producing stable engineered tissue for cartilage regeneration.
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Nikkholgh, Ahad, Fatemeh Tavakoli, Nasrin Alborzi, and Fatemeh Araste. "Vitamin D Attenuates Cardiac Hypertrophy in Rats through mRNA Regulation of Interleukin-6 and Its Receptor." Research in Cardiovascular Medicine 12, no. 4 (2023): 123–28. http://dx.doi.org/10.4103/rcm.rcm_60_23.
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Abstract Context: Interleukin-6 (IL-6), a pro-inflammatory cytokine, plays an important role in the pathogenesis of myocardial hypertrophy. By integrating its membrane receptor complex (gp80), IL-6 activates the signal guidance components (gp130) and activates the hypertrophic signaling pathways. There is some evidence that 1,25 dihydroxyvitamin D exerts antihypertrophic effects, but the cellular and molecular mechanisms are not fully understood. The aim of this study was to evaluate the effect of calcitriol on the level of IL-6 and its receptor components in hypertrophied rat heart. Subjects and Methods: Male rats were divided into control, hypertrophy, Vitamin D + hypertrophy, and propylene glycol + hypertrophy groups. The groups receiving Vitamin D and propylene glycol were treated 2 weeks before induction of hypertrophy and 2 weeks after hypertrophy. Myocardial hypertrophy was induced by abdominal aortic stenosis. Mean arterial blood pressure was measured by cannulation of the left carotid artery, and expression of genes was determined by reverse transcription-polymerase chain reaction. Results: Blood pressure and heart-to-body weight ratio increased in hypertrophic groups compared to the control group (P < 0.01), but Vitamin D administration decreased these parameters (P < 0.05). Abdominal aortic stenosis increased IL-6 expression levels (P < 0.001) and Vitamin-D decreased IL-6 mRNA levels (P < 0.01). The expression of gp80 in the hypertrophic group increased compared to the control group (P < 0.05), but Vitamin D did not affect the expression of receptor subunits genes. Conclusions: The data from this study suggest a possible mechanism for the antihypertrophic effects of Vitamin D through the regulation of inflammatory responses during hypertrophy. Thus, Vitamin D can reduce IL-6 expression levels, thereby reducing hypertrophy.
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Yan, Xiaoying, Ran Zhao, Xiaorong Feng, Jingzhou Mu, Ying Li, Yue Chen, Chunmei Li, et al. "Sialyltransferase7A promotes angiotensin II-induced cardiomyocyte hypertrophy via HIF-1α-TAK1 signalling pathway." Cardiovascular Research 116, no. 1 (March 11, 2019): 114–26. http://dx.doi.org/10.1093/cvr/cvz064.
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Abstract Aims Sialylation is up-regulated during the development of cardiac hypertrophy. Sialyltransferase7A (Siat7A) mRNA is consistently over-expressed in the hypertrophic left ventricle of hypertensive rats independently of genetic background. The aims of this study were: (i) to detect the Siat7A protein levels and its roles in the pathological cardiomyocyte hypertrophy; (ii) to elucidate the effect of sialylation mediated by Siat7A on the transforming-growth-factor-β-activated kinase (TAK1) expression and activity in cardiomyocyte hypertrophy; and (iii) to clarify hypoxia-inducible factor 1 (HIF-1) expression was regulated by Siat7A and transactivated TAK1 expression in cardiomyocyte hypertrophy. Methods and results Siat7A protein level was increased in hypertrophic cardiomyocytes of human and rats subjected to chronic infusion of angiotensin II (ANG II). Delivery of adeno-associated viral (AAV9) bearing shRNA against rat Siat7A into the left ventricular wall inhibited ventricular hypertrophy. Cardiac-specific Siat7A overexpression via intravenous injection of an AAV9 vector encoding Siat7A under the cardiac troponin T (cTNT) promoter aggravated cardiac hypertrophy in ANG II-treated rats. In vitro, Siat7A knockdown inhibited the induction of Sialyl-Tn (sTn) antigen and cardiomyocyte hypertrophy stimulated by ANG II. Mechanistically, ANG II induced the activation of TAK1-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling in parallel to up-regulation of Siat7A in hypertrophic cardiomyocytes. Siat7A knockdown inhibited activation of TAK1-NF-κB pathway. Interestingly, HIF-1α expression was increased in cardiomyocytes stimulated by ANG II but decreased after Siat7A knockdown. HIF-1α knockdown efficiently decreased TAK1 expression. ChIP and luciferase assays showed that HIF-1α transactivated the TAK1 promoter region (nt −1285 to −1274 bp) in the cardiomyocytes following ANG II stimulus. Conclusion Siat7A was up-regulated in hypertrophic myocardium and promoted cardiomyocyte hypertrophy via activation of the HIF-1α-TAK1-NF-κB pathway.
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Bazgir, Farhad, Julia Nau, Saeideh Nakhaei-Rad, Ehsan Amin, Matthew J. Wolf, Jeffry J. Saucerman, Kristina Lorenz, and Mohammad Reza Ahmadian. "The Microenvironment of the Pathogenesis of Cardiac Hypertrophy." Cells 12, no. 13 (July 4, 2023): 1780. http://dx.doi.org/10.3390/cells12131780.
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Pathological cardiac hypertrophy is a key risk factor for the development of heart failure and predisposes individuals to cardiac arrhythmia and sudden death. While physiological cardiac hypertrophy is adaptive, hypertrophy resulting from conditions comprising hypertension, aortic stenosis, or genetic mutations, such as hypertrophic cardiomyopathy, is maladaptive. Here, we highlight the essential role and reciprocal interactions involving both cardiomyocytes and non-myocardial cells in response to pathological conditions. Prolonged cardiovascular stress causes cardiomyocytes and non-myocardial cells to enter an activated state releasing numerous pro-hypertrophic, pro-fibrotic, and pro-inflammatory mediators such as vasoactive hormones, growth factors, and cytokines, i.e., commencing signaling events that collectively cause cardiac hypertrophy. Fibrotic remodeling is mediated by cardiac fibroblasts as the central players, but also endothelial cells and resident and infiltrating immune cells enhance these processes. Many of these hypertrophic mediators are now being integrated into computational models that provide system-level insights and will help to translate our knowledge into new pharmacological targets. This perspective article summarizes the last decades’ advances in cardiac hypertrophy research and discusses the herein-involved complex myocardial microenvironment and signaling components.
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Gallo, Simona, Annapia Vitacolonna, Alessandro Bonzano, Paolo Comoglio, and Tiziana Crepaldi. "ERK: A Key Player in the Pathophysiology of Cardiac Hypertrophy." International Journal of Molecular Sciences 20, no. 9 (May 1, 2019): 2164. http://dx.doi.org/10.3390/ijms20092164.
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Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity in cardiac hypertrophy. ERK signaling produces beneficial effects during the early phase of chronic pressure overload in response to G protein-coupled receptors (GPCRs) and integrin stimulation. These functions comprise (i) adaptive concentric hypertrophy and (ii) cell death prevention. On the other hand, ERK participates in maladaptive hypertrophy during hypertension and chemotherapy-mediated cardiac side effects. Specific ERK-associated scaffold proteins are implicated in either cardioprotective or detrimental hypertrophic functions. Interestingly, ERK phosphorylated at threonine 188 and activated ERK5 (the big MAPK 1) are associated with pathological forms of hypertrophy. Finally, we examine the connection between ERK activation and hypertrophy in (i) transgenic mice overexpressing constitutively activated RTKs (receptor tyrosine kinases), (ii) animal models with mutated sarcomeric proteins characteristic of inherited hypertrophic cardiomyopathies (HCMs), and (iii) mice reproducing syndromic genetic RASopathies. Overall, the scientific literature suggests that during cardiac hypertrophy, ERK could be a “good” player to be stimulated or a “bad” actor to be mitigated, depending on the pathophysiological context.
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Su, Dongmei, Sun Jing, Lina Guan, Qian Li, Huiling Zhang, Xiaobo Gao, and Xu Ma. "Role of Nodal–PITX2C signaling pathway in glucose-induced cardiomyocyte hypertrophy." Biochemistry and Cell Biology 92, no. 3 (June 2014): 183–90. http://dx.doi.org/10.1139/bcb-2013-0124.
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Pathological cardiac hypertrophy is a major cause of morbidity and mortality in cardiovascular disease. Recent studies have shown that cardiomyocytes, in response to high glucose (HG) stimuli, undergo hypertrophic growth. While much work still needs to be done to elucidate this important mechanism of hypertrophy, previous works have showed that some pathways or genes play important roles in hypertrophy. In this study, we showed that sublethal concentrations of glucose (25 mmol/L) could induce cardiomyocyte hypertrophy with an increase in the cellular surface area and the upregulation of the atrial natriuretic peptide (ANP) gene, a hypertrophic marker. High glucose (HG) treatments resulted in the upregulation of the Nodal gene, which is under-expressed in cardiomyocytes. We also determined that the knockdown of the Nodal gene resisted HG-induced cardiomyocyte hypertrophy. The overexpression of Nodal was able to induce hypertrophy in cardiomyocytes, which was associated with the upregulation of the PITX2C gene. We also showed that increases in the PITX2C expression, in response to Nodal, were mediated by the Smad4 signaling pathway. This study is highly relevant to the understanding of the effects of the Nodal–PITX2C pathway on HG-induced cardiomyocyte hypertrophy, as well as the related molecular mechanisms.
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Hernández Quiles, C., and L. M. Beltrán Romero. "Hypertrophic cardiomyopathy: Beyond left ventricular hypertrophy." Revista Clínica Española (English Edition) 221, no. 6 (June 2021): 343–44. http://dx.doi.org/10.1016/j.rceng.2020.03.005.
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SUN, XUE-FENG, QING-JUN WU, YA-LAN BI, YONG HOU, MENG-TAO LI, WEN ZHANG, XUAN ZHANG, et al. "Primary Hypertrophic Osteoarthropathy with Gastric Hypertrophy." Journal of Rheumatology 38, no. 5 (May 2011): 959–60. http://dx.doi.org/10.3899/jrheum.101077.
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Silver, Meredith M., and Malcolm D. Silver. "Left ventricular hypertrophy versus hypertrophic cardlomyopathy." Journal of Pediatrics 121, no. 3 (September 1992): 500–501. http://dx.doi.org/10.1016/s0022-3476(05)81824-4.
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Borer, Jeffrey S. "Left ventricular hypertrophy in hypertrophic cardiomyopathy." Journal of the American College of Cardiology 44, no. 2 (July 2004): 406–8. http://dx.doi.org/10.1016/j.jacc.2004.04.023.
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Xie, Xin, Hai-Lian Bi, Song Lai, Yun-Long Zhang, Nan Li, Hua-Jun Cao, Ling Han, Hong-Xia Wang, and Hui-Hua Li. "The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation." Science Advances 5, no. 5 (May 2019): eaau0495. http://dx.doi.org/10.1126/sciadv.aau0495.
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Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. The immunoproteasome is an inducible form of the proteasome that is intimately involved in inflammatory diseases. Here, we found that the expression and activity of immunoproteasome catalytic subunit β5i were significantly up-regulated in angiotensin II (Ang II)–treated cardiomyocytes and in the hypertrophic hearts. Knockout of β5i in cardiomyocytes and mice markedly attenuated the hypertrophic response, and this effect was aggravated by β5i overexpression in cardiomyocytes and transgenic mice. Mechanistically, β5i interacted with and promoted ATG5 degradation thereby leading to inhibition of autophagy and cardiac hypertrophy. Further, knockdown of ATG5 or inhibition of autophagy reversed the β5i knockout-mediated reduction of cardiomyocyte hypertrophy induced by Ang II or pressure overload. Together, this study identifies a novel role for β5i in the regulation of cardiac hypertrophy. The inhibition of β5i activity may provide a new therapeutic approach for hypertrophic diseases.
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Gao, Si, Xue-ping Liu, Li-hua Wei, Jing Lu, and Peiqing Liu. "Upregulation of α-enolase protects cardiomyocytes from phenylephrine-induced hypertrophy." Canadian Journal of Physiology and Pharmacology 96, no. 4 (April 2018): 352–58. http://dx.doi.org/10.1139/cjpp-2017-0282.
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Cardiac hypertrophy often refers to the abnormal growth of heart muscle through a variety of factors. The mechanisms of cardiomyocyte hypertrophy have been extensively investigated using neonatal rat cardiomyocytes treated with phenylephrine. α-Enolase is a glycolytic enzyme with “multifunctional jobs” beyond its catalytic activity. Its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the change of α-enolase during cardiac hypertrophy and explore its role in this pathological process. We revealed that mRNA and protein levels of α-enolase were significantly upregulated in hypertrophic rat heart induced by abdominal aortic constriction and in phenylephrine-treated neonatal rat cardiomyocytes. Furthermore, knockdown of α-enolase by RNA interference in cardiomyocytes mimicked the hypertrophic responses and aggravated phenylephrine-induced hypertrophy without reducing the total glycolytic activity of enolase. In addition, knockdown of α-enolase led to an increase of GATA4 expression in the normal and phenylephrine-treated cardiomyocytes. Our results suggest that the elevation of α-enolase during cardiac hypertrophy is compensatory. It exerts a catalytic independent role in protecting cardiomyocytes against pathological hypertrophy.
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Zhang, Yan, Qiang Da, Siyi Cao, Ke Yan, Zhiguang Shi, Qing Miao, Chen Li, et al. "HINT1 (Histidine Triad Nucleotide-Binding Protein 1) Attenuates Cardiac Hypertrophy Via Suppressing HOXA5 (Homeobox A5) Expression." Circulation 144, no. 8 (August 24, 2021): 638–54. http://dx.doi.org/10.1161/circulationaha.120.051094.
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Background: Cardiac hypertrophy is an important prepathology of, and will ultimately lead to, heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. This study aims to elucidate the effects and mechanisms of HINT1 (histidine triad nucleotide–binding protein 1) in cardiac hypertrophy and heart failure. Methods: HINT1 was downregulated in human hypertrophic heart samples compared with nonhypertrophic samples by mass spectrometry analysis. Hint1 knockout mice were challenged with transverse aortic constriction surgery. Cardiac-specific overexpression of HINT1 mice by intravenous injection of adeno-associated virus 9 (AAV9)–encoding Hint1 under the cTnT (cardiac troponin T) promoter were subjected to transverse aortic construction. Unbiased transcriptional analyses were used to identify the downstream targets of HINT1. AAV9 bearing shRNA against Hoxa5 (homeobox A5) was administrated to investigate whether the effects of HINT1 on cardiac hypertrophy were HOXA5-dependent. RNA sequencing analysis was performed to recapitulate possible changes in transcriptome profile.Coimmunoprecipitation assays and cellular fractionation analyses were conducted to examine the mechanism by which HINT1 regulates the expression of HOXA5. Results: The reduction of HINT1 expression was observed in the hearts of hypertrophic patients and pressure overloaded–induced hypertrophic mice, respectively. In Hint1 -deficient mice, cardiac hypertrophy deteriorated after transverse aortic construction. Conversely, cardiac-specific overexpression of HINT1 alleviated cardiac hypertrophy and dysfunction. Unbiased profiler polymerase chain reaction array showed HOXA5 is 1 target for HINT1, and the cardioprotective role of HINT1 was abolished by HOXA5 knockdown in vivo. Hoxa5 was identified to affect hypertrophy through the TGF-β (transforming growth factor β) signal pathway. Mechanically, HINT1 inhibited PKCβ1 (protein kinase C β type 1) membrane translocation and phosphorylation via direct interaction, attenuating the MEK/ERK/YY1 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/yin yang 1) signal pathway, downregulating HOXA5 expression, and eventually attenuating cardiac hypertrophy. Conclusions: HINT1 protects against cardiac hypertrophy through suppressing HOXA5 expression. These findings indicate that HINT1 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.
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Liu, Yang, Shuang Li, Zhanqun Gao, Shuangjia Li, Qingyun Tan, Yanmei Li, Dongwei Wang, and Qingdong Wang. "Indoleamine 2,3-Dioxygenase 1 (IDO1) Promotes Cardiac Hypertrophy via a PI3K-AKT-mTOR-Dependent Mechanism." Cardiovascular Toxicology 21, no. 8 (May 21, 2021): 655–68. http://dx.doi.org/10.1007/s12012-021-09657-y.
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AbstractIndoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme for tryptophan metabolism, involved in immune cell differentiation/maturation and cancer biology. IDO1 is also expressed in cardiomyocytes, but its roles in the cardiovascular system are not fully understood. Here, we reported the functions of IDO1 during cardiac hypertrophy. Quantitative real-time PCR and Western blot experiments demonstrated the upregulation of IDO1 mRNA and protein levels in human and hypertrophic mouse hearts, as well as in angiotensin II (Ang II)-induced hypertrophic rat cardiomyocytes. IDO1 activity and metabolite product kynurenine were upregulated in rodent hypertrophic hearts and cardiomyocytes. Inhibition of IDO1 activity with PF-06840003 reduced Ang II-induced cardiac hypertrophy and rescued cardiac function in mice. siRNA-mediated knockdown of Ido1 repressed Ang II-induced growth in cardiomyocyte size and overexpression of hypertrophy-associated genes atrial natriuretic peptide (Anp or Nppa), brain natriuretic peptide (Bnp or Nppb), β-myosin heavy chain (β-Mhc or Myh7). By contrast, adenovirus-mediated rat Ido1 overexpression in cardiomyocytes promoted hypertrophic growth induced by Ang II. Mechanism analysis showed that IDO1 overexpression was associated with PI3K-AKT-mTOR signaling to activate the ribosomal protein S6 kinase 1 (S6K1), which promoted protein synthesis in Ang II-induced hypertrophy of rat cardiomyocytes. Finally, we provided evidence that inhibition of PI3K with pictilisib, AKT with perifosine, or mTOR with rapamycin, blocked the effects of IDO1 on protein synthesis and cardiomyocyte hypertrophy in Ang II-treated cells. Collectively, our findings identify that IDO1 promotes cardiomyocyte hypertrophy partially via PI3K-AKT-mTOR-S6K1 signaling.
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Li, Yu, Bo He, Chao Zhang, Yanji He, Tianyang Xia, and Chunyu Zeng. "Naringenin Attenuates Isoprenaline-Induced Cardiac Hypertrophy by Suppressing Oxidative Stress through the AMPK/NOX2/MAPK Signaling Pathway." Nutrients 15, no. 6 (March 9, 2023): 1340. http://dx.doi.org/10.3390/nu15061340.
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Cardiac hypertrophy is accompanied by increased myocardial oxidative stress, and whether naringenin, a natural antioxidant, is effective in the therapy of cardiac hypertrophy remains unknown. In the present study, different dosage regimens (25, 50, and 100 mg/kg/d for three weeks) of naringenin (NAR) were orally gavaged in an isoprenaline (ISO) (7.5mg/kg)-induced cardiac hypertrophic C57BL/6J mouse model. The administration of ISO led to significant cardiac hypertrophy, which was alleviated by pretreatment with naringenin in both in vivo and in vitro experiments. Naringenin inhibited ISO-induced oxidative stress, as demonstrated by the increased SOD activity, decreased MDA level and NOX2 expression, and inhibited MAPK signaling. Meanwhile, after the pretreatment with compound C (a selective AMPK inhibitor), the anti-hypertrophic and anti-oxidative stress effects of naringenin were blocked, suggesting the protective effect of naringenin on cardiac hypertrophy. Our present study indicated that naringenin attenuated ISO-induced cardiac hypertrophy by regulating the AMPK/NOX2/MAPK signaling pathway.
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Tang, Xin, Lihong Pan, Shuang Zhao, Feiyue Dai, Menglin Chao, Hong Jiang, Xuesong Li, et al. "SNO-MLP (S-Nitrosylation of Muscle LIM Protein) Facilitates Myocardial Hypertrophy Through TLR3 (Toll-Like Receptor 3)–Mediated RIP3 (Receptor-Interacting Protein Kinase 3) and NLRP3 (NOD-Like Receptor Pyrin Domain Containing 3) Inflammasome Activation." Circulation 141, no. 12 (March 24, 2020): 984–1000. http://dx.doi.org/10.1161/circulationaha.119.042336.
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Background: S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of SNO of MLP (muscle LIM protein) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload. Methods: Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. SNO sites were further identified through liquid chromatography–tandem mass spectrometry. Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry and confirmed by coimmunoprecipitation. Recruitment of TLR3 (Toll-like receptor 3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA–transfected neonatal rat cardiomyocytes and in a TLR3 knockout mouse model. Results: SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction. The level of SNO-MLP also increased in angiotensin II– or phenylephrine-treated neonatal rat cardiomyocytes. S-nitrosylated site of MLP at cysteine 79 was identified by liquid chromatography–tandem mass spectrometry and confirmed in neonatal rat cardiomyocytes. Mutation of cysteine 79 significantly reduced hypertrophic growth in angiotensin II– or phenylephrine-treated neonatal rat cardiomyocytes and transverse aortic constriction mice. Reducing SNO-MLP level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, SNO-MLP stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupted this interaction by downregulating TLR3-attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and RIP3 (receptor-interacting protein kinase 3). This interaction in turn induced NLRP3 (nucleotide-binding oligomerization domain–like receptor pyrin domain containing 3) inflammasome activation, thereby promoting the development of myocardial hypertrophy. Conclusions: Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a therapeutic target for myocardial hypertrophy and heart failure.
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Liu, Yao-Lung, Chiu-Ching Huang, Chiz-Chung Chang, Che-Yi Chou, Shih-Yi Lin, I.-Kuan Wang, Dennis Jine-Yuan Hsieh, Gwo-Ping Jong, Chih-Yang Huang, and Chao-Min Wang. "Hyperphosphate-Induced Myocardial Hypertrophy through the GATA-4/NFAT-3 Signaling Pathway Is Attenuated by ERK Inhibitor Treatment." Cardiorenal Medicine 5, no. 2 (2015): 79–88. http://dx.doi.org/10.1159/000371454.
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Background/Aims: Numerous epidemiological studies have associated elevated serum phosphorus levels with cardiovascular disease and the risk of death in the general population as well as in chronic kidney disease (CKD) and dialysis patients. In this study, we explored whether elevated phosphate conditions induce cardiac hypertrophy and attempted to identify the molecular and cellular mechanisms in the hypertrophic response. Methods: H9c2 myocardial cells were incubated in high-phosphate conditions to induce hypertrophy. Pathological hypertrophic responses were measured in terms of cell size, arrangement of actin filaments, and hypertrophy markers such as atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in myocardial cells. Several transcriptional factors involved in cardiac hypertrophy development were measured to investigate the molecular pathways involved in elevated phosphate-induced cardiac hypertrophy. Results: High-phosphate conditions induced cellular hypertrophy, marked by increased cell size, reorganization of actin filaments, and upregulation of both ANP and BNP in H9c2 cells. Both upstream calcineurin and downstream transcription factors, including GATA-4 and NFAT-3, were significantly increased under hyperphosphate conditions. Moreover, both MEK1/2 and ERK1/2 expression increased significantly, and cellular hypertrophy was markedly attenuated by U0126, an ERK1/2 inhibitor. Conclusions: These results suggest that hyperphosphate conditions induce myocardial hypertrophy through the ERK signaling pathway in H9c2 cells. Our findings provide a link between the hyperphosphate-induced response and the ERK/NFAT-3 signaling pathway that mediates the development of cardiac hypertrophy. In view of the potent and selective activity of the ERK inhibitor U0126, this agent warrants further investigation as a candidate for preventing hyperphosphate-induced cardiac hypertrophy in CKD and dialysis patients.
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Li, Yuhao, Yoshihiko Saito, Koichiro Kuwahara, Xianglu Rong, Ichiro Kishimoto, Masaki Harada, Yuichiro Adachi, et al. "Guanylyl Cyclase-A Inhibits Angiotensin II Type 2 Receptor-Mediated Pro-Hypertrophic Signaling in the Heart." Endocrinology 150, no. 8 (April 16, 2009): 3759–65. http://dx.doi.org/10.1210/en.2008-1353.
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Angiotensin II plays a key role in the development of cardiac hypertrophy. The contribution of the angiotensin II type 1 receptor (AT1) in angiotensin II-induced cardiac hypertrophy is well established, but the role of AT2 signaling remains controversial. Previously, we have shown that natriuretic peptide receptor/guanylyl cyclase-A (GCA) signaling protects the heart from hypertrophy at least in part by inhibiting AT1-mediated pro-hypertrophic signaling. Here, we investigated the role of AT2 in cardiac hypertrophy observed in mice lacking GCA. Real-time RT-PCR and immunoblotting approaches indicated that the cardiac AT2 gene was overexpressed in GCA-deficient mice. Mice lacking AT2 alone did not exhibit an abnormal cardiac phenotype. In contrast, GCA-deficiency-induced increases in heart to body weight ratio, cardiomyocyte cross-sectional area, and collagen accumulation as evidenced by van Gieson staining were attenuated when AT2 was absent. Furthermore, the up-regulated cardiac expression of hypertrophy-related genes in GCA-null animals was also suppressed. Pharmacological blockade of AT2 with PD123319 similarly attenuated cardiac hypertrophy in GCA-deficient mice. In addition, whereas the AT1 antagonist olmesartan attenuated cardiac hypertrophy in GCA-deficient mice, this treatment was without effect on cardiac hypertrophy in GCA/AT2-double null mice, notwithstanding its potent antihypertensive effect in these animals. These results suggest that the interplay of AT2 and AT1 may be important in the development of cardiac hypertrophy. Collectively, our findings support the assertion that GCA inhibits AT2-mediated pro-hypertrophic signaling in heart and offer new insights into endogenous cardioprotective mechanisms during disease pathogenesis.
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Goodman, Craig A., Man Hing Miu, John W. Frey, Danielle M. Mabrey, Hannah C. Lincoln, Yejing Ge, Jie Chen, and Troy A. Hornberger. "A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy." Molecular Biology of the Cell 21, no. 18 (September 15, 2010): 3258–68. http://dx.doi.org/10.1091/mbc.e10-05-0454.
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It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used rapamycin to inhibit mTOR; yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB-independent activation of mTOR signaling, and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants also were used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy, and the kinase activity of mTOR is necessary for this event.
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Wehbe, Nadine, Suzanne Nasser, Gianfranco Pintus, Adnan Badran, Ali Eid, and Elias Baydoun. "MicroRNAs in Cardiac Hypertrophy." International Journal of Molecular Sciences 20, no. 19 (September 23, 2019): 4714. http://dx.doi.org/10.3390/ijms20194714.
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Like other organs, the heart undergoes normal adaptive remodeling, such as cardiac hypertrophy, with age. This remodeling, however, is intensified under stress and pathological conditions. Cardiac remodeling could be beneficial for a short period of time, to maintain a normal cardiac output in times of need; however, chronic cardiac hypertrophy may lead to heart failure and death. MicroRNAs (miRNAs) are known to have a role in the regulation of cardiac hypertrophy. This paper reviews recent advances in the field of miRNAs and cardiac hypertrophy, highlighting the latest findings for targeted genes and involved signaling pathways. By targeting pro-hypertrophic genes and signaling pathways, some of these miRNAs alleviate cardiac hypertrophy, while others enhance it. Therefore, miRNAs represent very promising potential pharmacotherapeutic targets for the management and treatment of cardiac hypertrophy.
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Johansson, Markus, Benyapa Tangruksa, Sepideh Heydarkhan-Hagvall, Anders Jeppsson, Peter Sartipy, and Jane Synnergren. "Data Mining Identifies CCN2 and THBS1 as Biomarker Candidates for Cardiac Hypertrophy." Life 12, no. 5 (May 12, 2022): 726. http://dx.doi.org/10.3390/life12050726.
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Cardiac hypertrophy is a condition that may contribute to the development of heart failure. In this study, we compare the gene-expression patterns of our in vitro stem-cell-based cardiac hypertrophy model with the gene expression of biopsies collected from hypertrophic human hearts. Twenty-five differentially expressed genes (DEGs) from both groups were identified and the expression of selected corresponding secreted proteins were validated using ELISA and Western blot. Several biomarkers, including CCN2, THBS1, NPPA, and NPPB, were identified, which showed significant overexpressions in the hypertrophic samples in both the cardiac biopsies and in the endothelin-1-treated cells, both at gene and protein levels. The protein-interaction network analysis revealed CCN2 as a central node among the 25 overlapping DEGs, suggesting that this gene might play an important role in the development of cardiac hypertrophy. GO-enrichment analysis of the 25 DEGs revealed many biological processes associated with cardiac function and the development of cardiac hypertrophy. In conclusion, we identified important similarities between ET-1-stimulated human-stem-cell-derived cardiomyocytes and human hypertrophic cardiac tissue. Novel putative cardiac hypertrophy biomarkers were identified and validated on the protein level, lending support for further investigations to assess their potential for future clinical applications.
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Preveden, Andrej, Mirna Usorac, Mirko Todic, Mihaela Preveden, Miodrag Golubovic, and Lazar Velicki. "Electrocardiographic features of patients with hypertrophic cardiomyopathy." Medical review 75, no. 1-2 (2022): 56–61. http://dx.doi.org/10.2298/mpns2202056p.
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Introduction. Hypertrophic cardiomyopathy is a disorder of the myocardium characterized by asymmetric or symmetric left ventricular hypertrophy. It is often an inherited disorder with an autosomal dominant pattern. The aim of this study was to evaluate the electrocardiographic characteristics of patients with hypertrophic cardiomyopathy, as well as to assess the accuracy of current electrocardiographic criteria for left ventricular hypertrophy used as indicators of hypertrophic cardiomyopathy. Material and Methods. This retrospective study was conducted using hospital medical records of 42 patients with the diagnosis of hypertrophic cardiomyopathy. Detailed electrocardiography analysis, apart from all the usual parameters, included the calculation of indices used to diagnose left ventricular hypertrophy including Sokolow augmented vector left, Cornell voltage, Cornell product, and Sokolow-Lyon index. Results. Sinus rhythm was present in 95.2% of patients, while atrial fibrillation was found in 4.8%. The majority of patients presented with left axis deviation. A slight positive correlation was found between the Sokolow augmented vector left index and posterolateral wall thickness (r = 0.475; p < 0.05), and also between the Cornell voltage index and posterolateral wall thickness (r = 0.368; p < 0.05). A borderline positive correlation was found between the Cornell product index and posterolateral wall thickness (r = 0.290; p = 0.063). Interventricular septum thickness showed no significant correlation with any of the electrocardiographic indices of left ventricular hypertrophy. Conclusion. In patients with hypertrophic cardiomyopathy, the Sokolow augmented vector left and Cornell voltage indices were the best indicators of posterolateral wall hypertrophy, whereas none of the examined indices correlated well with the interventricular septum thickness.
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Prinz, Christian, Lothar Faber, Dieter Horstkotte, Hermann Körperich, Axel Moysich, Nikolaus Haas, Deniz Kececioglu, and Kai Thorsten Laser. "Evaluation of left ventricular torsion in children with hypertrophic cardiomyopathy." Cardiology in the Young 24, no. 2 (February 7, 2013): 245–52. http://dx.doi.org/10.1017/s104795111300005x.
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AbstractAimsTo evaluate the role of torsion in hypertrophic cardiomyopathy in children.MethodsA total of 88 children with idiopathic hypertrophic cardiomyopathy (n = 24) and concentric hypertrophy (n = 20) were investigated with speckle-tracking echocardiography and compared with age- and gender-matched healthy controls (n = 44).ResultsIn hypertrophic cardiomyopathy, we found increased torsion (2.8 ± 1.6 versus 1.9 ± 1.0°/cm [controls], p < 0.05) because of an increase in clockwise basal rotation (−8.7 ± 4.3° versus −4.9 ± 2.5° [controls], p < 0.001) and prolonged time to peak diastolic untwisting (3.7 ± 2.4% versus 1.7 ± 0.6% [controls] of cardiac cycle, p < 0.01), but no differences in peak untwisting velocities. Hypertrophic cardiomyopathy patients demonstrated a negative correlation between left ventricular muscle mass and torsion (r = −0.7, p < 0.001). In concentric hypertrophy, torsion was elevated because of increased apical rotation (15.1 ± 6.4° versus 10.5 ± 5.5° [controls], p < 0.05) without correlation with muscle mass. Peak untwisting velocities (− 202 ± 88 versus −145 ± 67°/s [controls], p < 0.05) were higher in concentric hypertrophy and time to peak diastolic untwisting was delayed (1.8 ± 0.8% versus 1.2 ± 0.6% [controls], p < 0.05).ConclusionsIn contrast to an increased counterclockwise apical rotation in concentric hypertrophy, hypertrophic cardiomyopathy is characterised by predominantly enhanced systolic basal clockwise rotation. Diastolic untwisting is delayed in both groups. Torsion may be an interesting marker to guide patients with hypertrophic cardiomyopathy.
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Khatoon, Razia, Swaimanti Sarkar, Aindrila Chattopadhyay, and Debasish Bandyopadhyay. "The cardioprotective potential of melatonin on cardiac hypertrophy: A mechanistic overview." Melatonin Research 6, no. 3 (September 30, 2023): 313–44. http://dx.doi.org/10.32794/mr112500157.
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Cardiac hypertrophy (CH) is an increment of muscle mass to maintain the heart regular operations. A physiological cardiac hypertrophy due to exercise or other normal physiological process is characterized by normal contractile function and structural framework of heart tissue. In contrast, pathological hypertrophy occurs in response to increased pressure or volume overload from several cardiovascular diseases including hypertension, valvular diseases, cardiac infarction and heart failure. It is of major concern as it is one of the leading causes of death worldwide. Despite much progress in this field there is a scope for understanding of the molecular mechanisms of this condition. In this review, various types of cardiac hypertrophy and their intricate physio-pathological mechanisms have been discussed. In addition, the genetic mutations in sarcomere genes and oxidative stress are also closely linked to hypertrophic cardiomyopathy. Although several drugs against cardiac hypertrophy have been used, it appears that melatonin, due to its high bioavailability and low side effects, is a better candidate than the conventional medicine for treatment of hypertrophic cardiomyopathy. Melatonin, a hormone and a potent antioxidant, is secreted mainly from the pineal gland, but it is also synthesized from different peripheral tissues including the heart. This molecule can regulate a myriad of cellular functions. It can protect against cardiac hypertrophy via reducing oxidative stress, elevating Cu-Mn SOD via controlling several cell signalling pathways of Akt/mTOR, ROR-α and NLRP3 cascades. Melatonin also mitigates cardiac hypertrophy by suppressing pro-inflammatory cytokines including TNF-α and TGF-β and cardiac hypertrophy markers like β-MHC, ANP, BNP, LDH. This review focuses on the molecular mechanisms of cardiac hypertrophy and the defensive role of melatonin on it. We propose melatoninas a propitious adjunct for the treatment of cardiac hypertrophy.
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Quddus, Sharmin, Tapati Mandal, Sharmin Reza, Nasreen Sultana, Rahima Parveen, Urnus Islam, and Sadia Sultana. "SPECT Myocardial Perfusion Imaging in the Diagnosis of Apical Hypertrophic Cardiomyopathy- Case Series and Literature Review." Bangladesh Journal of Nuclear Medicine 27, no. 1 (June 23, 2024): 100–106. http://dx.doi.org/10.3329/bjnm.v27i1.71520.
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Apical hypertrophic cardiomyopathy (AHCM) is a subtype of hypertrophic cardiomyopathy (HCM) in which hypertrophy mostly affects the apex of the left ventricle, resulting in mid-ventricular obstruction. The diagnosis is usually made when the LV apex has an apical wall thickness of ≥ 15 mm in echocardiography, though sometimes it is missed due to the poor acoustic window in two-dimensional echocardiography. Single Photon Emission Computed Tomography-Myocardial Perfusion Imaging (SPECT-MPI) can often detect apical hypertrophy. The apical hypertrophy was identified by SPECT-MPI in the reported three cases, which were not previously diagnosed by echocardiography. Bangladesh J. Nuclear Med. 27(1): 100-106, 2024
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Hu, Chengyun, Feibiao Dai, Jiawu Wang, Lai Jiang, Di Wang, Jie Gao, Jun Huang, et al. "Peroxiredoxin-5 Knockdown Accelerates Pressure Overload-Induced Cardiac Hypertrophy in Mice." Oxidative Medicine and Cellular Longevity 2022 (January 29, 2022): 1–12. http://dx.doi.org/10.1155/2022/5067544.
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A recent study showed that peroxiredoxins (Prxs) play an important role in the development of pathological cardiac hypertrophy. However, the involvement of Prx5 in cardiac hypertrophy remains unclear. Therefore, this study is aimed at investigating the role and mechanisms of Prx5 in pathological cardiac hypertrophy and dysfunction. Transverse aortic constriction (TAC) surgery was performed to establish a pressure overload-induced cardiac hypertrophy model. In this study, we found that Prx5 expression was upregulated in hypertrophic hearts and cardiomyocytes. In addition, Prx5 knockdown accelerated pressure overload-induced cardiac hypertrophy and dysfunction in mice by activating oxidative stress and cardiomyocyte apoptosis. Importantly, heart deterioration caused by Prx5 knockdown was related to mitogen-activated protein kinase (MAPK) pathway activation. These findings suggest that Prx5 could be a novel target for treating cardiac hypertrophy and heart failure.
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Wang, Yao-Sheng, Jing Zhou, Kui Hong, Xiao-Shu Cheng, and Yi-Gang Li. "MicroRNA-223 Displays a Protective Role Against Cardiomyocyte Hypertrophy by Targeting Cardiac Troponin I-Interacting Kinase." Cellular Physiology and Biochemistry 35, no. 4 (2015): 1546–56. http://dx.doi.org/10.1159/000373970.
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Background/Aims: MicroRNAs play regulatory role in cardiovascular disease. MicroRNA-223 (miR-223) was found to be expressed abundantly in myocardium. TNNI3K, a novel cardiac troponin I (cTnI)-interacting and cardiac hypertrophy related kinase, is computationally predicted as a potential target of miR-223. This study was designed to investigate the cellular and molecular effects of miR-223 on cardiomyoctye hypertrophy, focusing on the role of TNNI3K. Methods: Neonatal rat cardiomyocytes (CMs) were cultured, and CMs hypertrophy was induced by endothelin-1 (ET-1). In vivo cardiac hypertrophy was induced by transverse aorta constriction (TAC) in rats. Expression of miR-223 in CMs and myocardium was detected by real-time PCR (RT-PCR). MiR-223 and TNNI3K were overexpressed in CMs via chemically modifed sense RNA (miR-223 mimic) transfection or recombinant adenovirus infection, respectively. Cell size was measured by surface area calculation using fluorescence microscopy after anti-α-actinin staining. Expression of hypertrophy-related genes was detected by RT-PCR. The protein expression of TNNI3K and cTnI was determined by Western blots. Luciferase assay was employed to confirm the direct binding of miR-223 to the 3'UTR of TNNI3K mRNA. Intracellular calcium was measured by sensitive fluorescent indicator (Furo-2). Video-based edge detection system was employed to measure cardiomyocyte contractility. Results: MiR-223 was downregulated in ET-1 induced hypertrophic CMs and in hypertrophic myocardium compared with respective controls. MiR-223 overexpression in CMs alleviated ET-1 induced hypertrophy, evidenced by smaller cell surface area and downregulated ANP, α-actinin, Myh6 and Myh7 expression. Luciferase reporter gene assay showed that TNNI3K serves as a direct target gene of miR-223. In miR-223-overexpressed CMs, the protein expression of TNNI3K was significantly downregulated. MiR-223 overexpression also rescued the upregulated TNNI3K expression in hypertrophic CMs. Furthermore, cTnI phosphorylation was downregulated post miR-223 overexpression. Ad.rTNNI3K increased intracellular Ca2+ concentrations and cell shortening in CMs, while miR-223 overexpression significantly rescued these hypertrophic effects. Conclusion: By direct targeting TNNI3K, miR-223 could suppress CMs hypertrophy via downregulating cTnI phosphorylation, reducing intracellular Ca2+ and contractility of CMs. miR-223 / TNNI3K axis may thus be major players of CMs hypertrophy.
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Lysova, I. V., and T. P. Senatorova. "Treatment of hypertrophic gingivitis with laser radiation." Kazan medical journal 69, no. 2 (April 15, 1988): 122. http://dx.doi.org/10.17816/kazmj97214.
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The treatment of hypertrophic gingivitis in adolescence is difficult and often accompanied by recurrences. There are recommendations on the exposure mode of the helium-neon laser, which inhibits cell proliferation with a photosensitizer, for the treatment of chronic hypertrophic gingivitis. We studied the efficacy of laser therapy in juvenile gingivitis. We treated 10 patients aged 16 to 18 years with the edematous form of hypertrophic gingivitis. Four of them had grade I hypertrophy of gingival papillae and six had grade II hypertrophy.
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Geraets, Ilvy M. E., Will A. Coumans, Agnieszka Strzelecka, Patrick Schönleitner, Gudrun Antoons, Francesco Schianchi, Myrthe M. A. Willemars, et al. "Metabolic Interventions to Prevent Hypertrophy-Induced Alterations in Contractile Properties In Vitro." International Journal of Molecular Sciences 22, no. 7 (March 31, 2021): 3620. http://dx.doi.org/10.3390/ijms22073620.
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(1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced cardiac hypertrophy for studying metabolic, structural, and functional changes over time. Accordingly, we investigated whether metabolic interventions prevent cardiac structural and functional changes; (2) Methods: Primary rat cardiomyocytes were treated with phenylephrine (PE) for 16 h, 24 h, or 48 h, whereafter hypertrophic marker expression, protein synthesis rate, glucose uptake, and contractile function were assessed; (3) Results: 24 h PE treatment increased expression of hypertrophic markers, phosphorylation of hypertrophy-related signaling kinases, protein synthesis, and glucose uptake. Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations; (4) Conclusions: Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction.
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Brown, Brittany F., Anita Quon, Jason R. B. Dyck, and Joseph R. Casey. "Carbonic anhydrase II promotes cardiomyocyte hypertrophy." Canadian Journal of Physiology and Pharmacology 90, no. 12 (December 2012): 1599–610. http://dx.doi.org/10.1139/y2012-142.
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Pathological cardiac hypertrophy, the maladaptive remodelling of the myocardium, often progresses to heart failure. The sodium–proton exchanger (NHE1) and chloride–bicarbonate exchanger (AE3) have been implicated as important in the hypertrophic cascade. Carbonic anhydrase II (CAII) provides substrates for these transporters (protons and bicarbonate, respectively). CAII physically interacts with NHE1 and AE3, enhancing their respective ion transport activities by increasing the concentration of substrate at their transport sites. Earlier studies found that a broad-spectrum carbonic anhydrase inhibitor prevented cardiomyocyte hypertrophy (CH), suggesting that carbonic anhydrase is important in the development of hypertrophy. Here we investigated whether cytosolic CAII was the CA isoform involved in hypertrophy. Neonatal rat ventricular myocytes (NRVMs) were transduced with recombinant adenoviral constructs to over-express wild-type or catalytically inactive CAII (CAII-V143Y). Over-expression of wild-type CAII in NRVMs did not affect CH development. In contrast, CAII-V143Y over-expression suppressed the response to hypertrophic stimuli, suggesting that CAII-V143Y behaves in a dominant negative fashion over endogenous CAII to suppress hypertrophy. We also examined CAII-deficient (Car2) mice, whose hearts exhibit physiological hypertrophy without any decrease in cardiac function. Moreover, cardiomyocytes from Car2 mice do not respond to prohypertrophic stimulation. Together, these findings support a role of CAII in promoting CH.
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Li, Peng-Long, Hui Liu, Guo-Peng Chen, Ling Li, Hong-Jie Shi, Hong-Yu Nie, Zhen Liu, et al. "STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) Inhibits Pathological Cardiac Hypertrophy." Hypertension 76, no. 4 (October 2020): 1219–30. http://dx.doi.org/10.1161/hypertensionaha.120.14752.
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Pathological cardiac hypertrophy is one of the major predictors and inducers of heart failure, the end stage of various cardiovascular diseases. However, the molecular mechanisms underlying pathogenesis of pathological cardiac hypertrophy remain largely unknown. Here, we provided the first evidence that STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) is a key negative regulator of this disease. We found that the expression of STEAP3 was reduced in pressure overload-induced hypertrophic hearts and phenylephrine-induced hypertrophic cardiomyocytes. In a transverse aortic constriction-triggered mouse cardiac hypertrophy model, STEAP3 deficiency remarkably deteriorated cardiac hypertrophy and fibrosis, whereas the opposite phenotype was observed in the cardiomyocyte-specific STEAP3 overexpressing mice. Accordingly, STEAP3 significantly mitigated phenylephrine-induced cell enlargement in primary neonatal rat cardiomyocytes. Mechanistically, via RNA-seq and immunoprecipitation-mass screening, we demonstrated that STEAP3 directly bond to Rho family small GTPase 1 and suppressed the activation of downstream mitogen-activated protein kinase-extracellular signal-regulated kinase signaling cascade. Remarkably, the antihypertrophic effect of STEAP3 was largely blocked by overexpression of constitutively active mutant Rac1 (G12V). Our study indicates that STEAP3 serves as a novel negative regulator of pathological cardiac hypertrophy by blocking the activation of the Rac1-dependent signaling cascade and may contribute to exploring effective therapeutic strategies of pathological cardiac hypertrophy treatment.
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Zhang, Haifeng, Shanshan Li, Qiulian Zhou, Qi Sun, Shutong Shen, Yanli Zhou, Yihua Bei, and Xinli Li. "Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p." Cellular Physiology and Biochemistry 38, no. 5 (2016): 1743–51. http://dx.doi.org/10.1159/000443113.
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Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has long been used to treat chronic heart failure. Previous studies demonstrated that QL could prevent cardiac remodeling and hypertrophy in response to hypertensive or ischemic stress. However, little is known about whether QL could modulate cardiac hypertrophy in vitro, and (if so) whether it is through modulation of specific hypertrophy-related microRNA. Methods: The primary neonatal rat ventricular cardiomyocytes were isolated, cultured, and treated with phenylephrine (PE, 50 µmol/L, 48 h) to induce hypertrophy in vitro, in the presence or absence of pretreatment with QL (0.5 µg/ml, 48 h). The cell surface area was determined by immunofluorescent staining for α-actinin. The mRNA levels of hypertrophic markers including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (MYH7) were assayed by qRT-PCRs. The protein synthesis of cardiomyocytes was determined by the protein/DNA ratio. The miR-199a-5p expression level was quantified in PE-treated cardiomyocytes and heart samples from acute myocardial infarction (AMI) mouse model. MiR-199a-5p overexpression was used to determine its role in the anti-hypertrophic effect of QL on cardiomyocytes. Results: PE induced obvious enlargement of cell surface in cardiomyocytes, paralleling with increased ANP, BNP, and MYH7 mRNA levels and elevated protein/DNA ratio. All these changes were reversed by the treatment with QL. Meanwhile, miR-199a-5p was increased in AMI mouse heart tissues. Of note, the increase of miR-199a-5p in PE-treated cardiomyocytes was reversed by the treatment with QL. Moreover, overexpression of miR-199a-5p abolished the anti-hypertrophic effect of QL on cardiomyocytes. Conclusion: QL prevents PE-induced cardiac hypertrophy. MiR-199a-5p is increased in cardiac hypertrophy, while reduced by treatment with QL. miR-199a-5p suppression is essential for the anti-hypertrophic effect of QL on cardiomyocytes.
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Yun, Ui Jeong, and Dong Kwon Yang. "Sinapic Acid Inhibits Cardiac Hypertrophy via Activation of Mitochondrial Sirt3/SOD2 Signaling in Neonatal Rat Cardiomyocytes." Antioxidants 9, no. 11 (November 21, 2020): 1163. http://dx.doi.org/10.3390/antiox9111163.
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Sinapic acid (SA) is a naturally occurring phenolic compound with antioxidant properties. It also has a wide range of pharmacological properties, such as anti-inflammatory, anticancer, and hepatoprotective properties. The present study aimed to evaluate the potential pharmacological effects of SA against hypertrophic responses in neonatal rat cardiomyocytes. In order to evaluate the preventive effect of SA on cardiac hypertrophy, phenylephrine (PE)-induced hypertrophic cardiomyocytes were treated with subcytotoxic concentrations of SA. SA effectively suppressed hypertrophic responses, such as cell size enlargement, sarcomeric rearrangement, and fetal gene re-expression. In addition, SA significantly inhibited the expression of mitogen-activated protein kinase (MAPK) proteins as pro-hypertrophic factors and protected the mitochondrial functions from hypertrophic stimuli. Notably, SA activated Sirt3, a mitochondrial deacetylase, and SOD2, a mitochondrial antioxidant, in hypertrophic cardiomyocytes. SA also inhibited oxidative stress in hypertrophic cardiomyocytes. However, the protective effect of SA was significantly reduced in Sirt3-silenced hypertrophic cardiomyocytes, indicating that SA exerts its beneficial effect through Sirt3/SOD signaling. In summary, this is the first study to reveal the potential pharmacological action and inhibitory mechanism of SA as an antioxidant against cardiac hypertrophy, suggesting that SA could be utilized for the treatment of cardiac hypertrophy.
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Bi, Hai-Lian, Xiao-Li Zhang, Yun-Long Zhang, Xin Xie, Yun-Long Xia, Jie Du, and Hui-Hua Li. "The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor." Science Advances 6, no. 16 (April 2020): eaax4826. http://dx.doi.org/10.1126/sciadv.aax4826.
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Pathological cardiac hypertrophy leads to heart failure (HF). The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role of deubiquitinating enzymes (DUBs) in cardiac function is limited. Here, we observed that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) was significantly up-regulated in agonist-stimulated primary cardiomyocytes and in hypertrophic and failing hearts. Knockdown of UCHL1 in cardiomyocytes and mouse hearts significantly ameliorated cardiac hypertrophy induced by agonist or pressure overload. Conversely, overexpression of UCHL1 had the opposite effect in cardiomyocytes and rAAV9-UCHL1–treated mice. Mechanistically, UCHL1 bound, deubiquitinated, and stabilized epidermal growth factor receptor (EGFR) and activated its downstream mediators. Systemic administration of the UCHL1 inhibitor LDN-57444 significantly reversed cardiac hypertrophy and remodeling. These findings suggest that UCHL1 positively regulates cardiac hypertrophy by stabilizing EGFR and identify UCHL1 as a target for hypertrophic therapy.
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Haq, Syed, Gabriel Choukroun, Zhao Bin Kang, Hardeep Ranu, Takashi Matsui, Anthony Rosenzweig, Jeffrey D. Molkentin, et al. "Glycogen Synthase Kinase-3β Is a Negative Regulator of Cardiomyocyte Hypertrophy." Journal of Cell Biology 151, no. 1 (October 2, 2000): 117–30. http://dx.doi.org/10.1083/jcb.151.1.117.
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Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3β (GSK-3β), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase–dependent protein kinase that phosphorylates GSK-3β on ser 9. Using adenovirus-mediated gene transfer of GSK-3β containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3β is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3β regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3β as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.
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Kang, Peter M., Patrick Yue, Zhilin Liu, Oleg Tarnavski, Natalya Bodyak, and Seigo Izumo. "Alterations in apoptosis regulatory factors during hypertrophy and heart failure." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 1 (July 2004): H72—H80. http://dx.doi.org/10.1152/ajpheart.00556.2003.
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Cardiac hypertrophy from pathological stimuli often proceeds to heart failure, whereas cardiac hypertrophy from physiological stimuli does not. In this study, physiological hypertrophy was created by a daily exercise regimen and pathological hypertrophy was created from a high-salt diet in Dahl salt-sensitive rats. The rats continued on a high-salt diet progressed to heart failure associated with an increased rate of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. We analyzed primary cultures of these hearts and found that only cardiomyocytes made hypertrophic by a pathological stimulus show increased sensitivity to apoptosis. Examination of the molecular changes associated with these distinct types of hypertrophy revealed changes in Bcl-2 family members and caspases favoring survival during physiological hypertrophy. However, in pathological hypertrophy, there were more diffuse proapoptotic changes, including changes in Fas, the Bcl-2 protein family, and caspases. Therefore, we speculate that this increased sensitivity to apoptotic stimulation along with proapoptotic changes in the apoptosis program may contribute to the development of heart failure seen in pathological cardiac hypertrophy.
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Chen, Jian-Kang, Jianchun Chen, George Thomas, Sara C. Kozma, and Raymond C. Harris. "S6 kinase 1 knockout inhibits uninephrectomy- or diabetes-induced renal hypertrophy." American Journal of Physiology-Renal Physiology 297, no. 3 (September 2009): F585—F593. http://dx.doi.org/10.1152/ajprenal.00186.2009.
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Removal of one kidney stimulates synthesis of RNA and protein, with minimal DNA replication, in all nephron segments of the remaining kidney, resulting in cell growth (increase in cell size) with minimal cell proliferation (increase in cell number). In addition to the compensatory renal hypertrophy caused by nephron loss, pathophysiological renal hypertrophy can occur as a consequence of early uncontrolled diabetes. However, the molecular mechanism underlying renal hypertrophy in these conditions remains unclear. In the present study, we report that deletion of S6 kinase 1 (S6K1) inhibited renal hypertrophy seen following either contralateral nephrectomy or induction of diabetes. In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. Immunoblotting analysis revealed that S6K1−/− mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1−/− mice. Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1−/− and S6K1+/+ littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1−/− mice. The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60–70% of the hypertrophy seen in wild-type mice but failed to prevent the ∼10% hypertrophy seen in S6K1−/− mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2.