scholarly journals Deubiquitinase Inhibitor Auranofin Attenuated Cardiac Hypertrophy by Blocking NF-κB Activation

2018 ◽  
Vol 45 (6) ◽  
pp. 2421-2430 ◽  
Author(s):  
Ming Hu ◽  
Zhenhui Zhang ◽  
Bin Liu ◽  
Shuangwei Zhang ◽  
Renjie Chai ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Myocardial Cell ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Aortic Constriction ◽  
Cell Hypertrophy ◽  
Abdominal Aortic

Background/Aims: Cardiac hypertrophy is a major outcome and compensatory response of the cardiovascular system to hemodynamic and additional stress responses that ultimately lead to heart failure. Auranofin (Aur) has been used for treating rheumatic arthritis for several decades. Aur is a 19S proteasome-associated deubiquitinase inhibitor, and inhibition of the proteasome is speculated to reverse cardiac hypertrophy. However, the role of the deubiquitinases, especially 19S proteasome-associated deubiquitinases, in the regulation of cardiac remodeling remains poorly understood. The present study investigated the role of Aur in cardiac hypertrophy both in vitro and in vivo. Methods: Male Sprague–Dawley rats underwent abdominal aortic constriction to induce left ventricular hypertrophy. The neonatal rat primary myocardial cell hypertrophy model was induced by Ang II. Echocardiography, hematoxylin-eosin staining, Masson’s trichrome staining, immunochemistry, western blot analysis, a cell viability assay, and enzyme-linked immunosorbent assay were performed. Results: Aur significantly reduced the abdominal aortic constriction that led to left ventricular hypertrophy, reduced heart cavity expansion, and functional disorder, and thereby reduced fetal gene expression and attenuated cardiac fibrosis. Furthermore, Aur caused marked accumulation of ubiquitinated proteins and IκBα, as well as inactivation of NF-κB. This phenomenon was confirmed in the neonatal rat primary myocardial cell hypertrophy model. Conclusions: The present study indicated that Aur blocks the development of left ventricular hypertrophy induced by abdominal aortic constriction. This phenomenon might be attributed to inhibition of the 19S proteasome-associated deubiquitinase that can lead to aggregation of IκBα and inactivation of the NF-κB pathway. Thus, Aur could be a potential anti-cardiac hypertrophy agent.

scholarly journals Loss of Endothelial Hypoxia Inducible Factor‐Prolyl Hydroxylase 2 Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Left Ventricular Hypertrophy ◽  
Cardiac Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Hypoxia Inducible Factor ◽  
Left Ventricular ◽  
Sequencing Analysis ◽  
Dependent Manner

Background Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial PHD2 (prolyl‐4 hydroxylase 2)/hypoxia inducible factor (HIF) signaling in the pathogenesis of cardiac hypertrophy and heart failure remains elusive. Methods and Results Mice with Egln1 Tie2Cre ( Tie2 ‐Cre‐mediated deletion of Egln1 [encoding PHD2]) exhibited left ventricular hypertrophy evident by increased thickness of anterior and posterior wall and left ventricular mass, as well as cardiac fibrosis. Tamoxifen‐induced endothelial Egln1 deletion in adult mice also induced left ventricular hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1 Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF‐2α as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF‐2α attenuated cardiac hypertrophy and fibrosis in Egln1 Tie2Cre mice. Conclusions The present study defines for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in an HIF‐2α–dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF‐2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

scholarly journals miR-139-5p inhibits isoproterenol-induced cardiac hypertrophy by targetting c-Jun

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Su Ming ◽  
Wang Shui-yun ◽  
Qiu Wei ◽  
Li Jian-hui ◽  
Hui Ru-tai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Monogenic Disease ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Rat Cardiomyocytes ◽  
Neonatal Rat Cardiomyocytes ◽  
Regulatory Effects

Hypertrophic cardiomyopathy (HCM) is a serious monogenic disease characterized by cardiac hypertrophy, fibrosis, sudden cardiac death, and heart failure. Previously, we identified that miR-139-5p was down-regulated in HCM patients. However, the regulatory effects of miR-139-5p remain unclear. Thus, we investigated the role of miR-139-5p in the regulation of cardiac hypertrophy. The expression of miR-139-5p in left ventricular tissues in HCM patients and mice subjected to transverse aortic constriction (TAC) was significantly down-regulated. Knockdown of miR-139-5p expression in neonatal rat cardiomyocytes (NRCMs) induced cardiomyocyte enlargement and increased atrial natriuretic polypeptide (ANP) expression. Overexpression of miR-139-5p antagonized isoproterenol (ISO)-induced cardiomyocyte enlargement and ANP/brain natriuretic peptide (BNP) up-regulation. More importantly, we found that c-Jun expression was inhibited by miR-139-5p in NRCMs. Knockdown of c-Jun expression significantly attenuated cardiac hypertrophy induced by miR-139-5p deprivation. Our data indicated that miR-139-5p was down-regulated in the hearts of HCM patients and that it inhibited cardiac hypertrophy by targetting c-Jun expression.

Ameliorative role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats

2014 ◽  
Vol 25 (4) ◽  
pp. 725-730 ◽  
Author(s):  
Amrit Pal Singh ◽  
Randhir Singh ◽  
Pawan Krishan
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Left Ventricular ◽  
High Density Lipoproteins ◽  
Peroxisome Proliferator ◽  
Aortic Constriction ◽  
Abdominal Aortic ◽  
Significant Change

AbstractFibrates are peroxisome proliferator-activated receptor-α agonists and are clinically used for treatment of dyslipidemia and hypertriglyceridemia. Fenofibrate is reported as a cardioprotective agent in various models of cardiac dysfunction; however, limited literature is available regarding the role of gemfibrozil as a possible cardioprotective agent, especially in a non-obese model of cardiac remodelling. The present study investigated the role of gemfibrozil against partial abdominal aortic constriction-induced cardiac hypertrophy in rats. Cardiac hypertrophy was induced by partial abdominal aortic constriction in rats and they survived for 4 weeks. The cardiac hypertrophy was assessed by measuring left ventricular weight to body weight ratio, left ventricular wall thickness, and protein and collagen content. The oxidative stress in the cardiac tissues was assessed by measuring thiobarbituric acid-reactive substances, superoxide anion generation, and reduced glutathione level. The haematoxylin–eosin and picrosirius red staining was used to observe cardiomyocyte diameter and collagen deposition, respectively. Moreover, serum levels of cholesterol, high-density lipoproteins, triglycerides, and glucose were also measured. Gemfibrozil (30 mg/kg, p.o.) was administered since the first day of partial abdominal aortic constriction and continued for 4 weeks. The partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy are indicated by significant change in various parameters used in the present study that were ameliorated with gemfibrozil treatment in rats. No significant change in serum parameters was observed between various groups used in the present study. It is concluded that gemfibrozil ameliorates partial abdominal aortic constriction-induced cardiac oxidative stress and hypertrophy and in rats.

Abstract 313: STIM1 Silencing Reverses Pressure-overload Induced Cardiac Hypertrophy In Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ludovic O Bénard ◽  
Daniel S Matasic ◽  
Mathilde Keck ◽  
Anne-Marie Lompré ◽  
Roger J Hajjar ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Aortic Banding ◽  
Cross Section Area ◽  
Abdominal Aortic ◽  
Section Area

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We demonstrated that STIM1 silencing prevented the development of left ventricular hypertrophy (LVH) in rats after abdominal aortic banding. Our aim was to study the role of STIM1 during the transition from LVH to heart failure (HF). For experimental timeline, see figure. Transverse Aortic Constriction (TAC) was performed in C57Bl/6 mice. In vivo gene silencing was performed using recombinant Associated AdenoVirus 9 (AAV9). Mice were injected with saline or with AAV9 expressing shRNA control or against STIM1 (shSTIM1) (dose: 1e+11 viral genome), which decreased STIM1 cardiac expression by 70% compared to control. While cardiac parameters were similar between the TAC groups at weeks 3 and 6, shSTIM1 animals displayed a progressive and total reversion of LVH with LV walls thickness returning to values observed in sham mice at week 8. This reversion was associated with the development of significant LV dilation and severe contractile dysfunction, as assessed by echography. Hemodynamic analysis confirmed the altered contractile function and dilation of shSTIM1 animals. Immunohistochemistry showed a trend to more fibrosis. Despite hypertrophic stimuli, there was a significant reduction in cardiac myocytes cross-section area in shSTIM1-treated animals as compared to other TAC mice. This study showed that STIM1 is essential to maintain compensatory LVH and that its silencing accelerates the transition to HF.

Role of Calcineurin-Dependent Signaling Pathway on the Left Ventricular Hypertrophy Induced by Pressure Overload

2001 ◽  
Vol 31 (11) ◽  
pp. 1159
Author(s):  
Hainan Piao ◽  
Jin Sook Kwon ◽  
Hye Young Lee ◽  
Tae Jin Youn ◽  
Dong Woon Kim ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Signaling Pathway ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Dependent Signaling Pathway
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