Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis

Abstract

Endoplasmic reticulum (ER) stress is implicated in the pathophysiology of various cardiovascular diseases, but the role of ER stress in cardiac rupture and/or remodeling after myocardial infarction (MI) is still unclear. Here we investigated whether ER stress plays a major role for these processes in mice. We ligated the left coronary artery (LCA) without reperfusion in mice and administered either NaCl or 4-phenylbutyric acid (4-PBA, 20 mg/kg/d) intraperitoneally for 4 weeks. Cardiac rupture rates during the first week of MI were 37.5% and 18.2% in the control and 4-PBA groups, respectively. The extent of ventricular aneurysm and fibrosis was less, and the cardiac function better, in the 4-PBA group compared with the control group. The protein levels of ER stress markers in the heart tissues of the control group remained elevated during the entire 4-week period after MI, while pro-apoptotic proteins mainly increased in the early phase, and the pro-fibrotic proteins markedly increased in the late phase post MI; 4-PBA decreased all of these protein levels. In the primary cultured neonatal rat cardiomyocytes or fibroblasts, hypoxia (3% O 2 ) increased the number of apoptotic cardiomyocytes and promoted the proliferation and migration of fibroblasts, all of which were attenuated by 4-PBA (0.5 mM). These findings indicate that MI induces ER stress and provokes cardiac apoptosis and fibrosis, culminating in cardiac rupture and remodeling,

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

“…4-PBA was able to reduce ER stress factors, mitigate ISO-induced cardiac damage, and prevent interstitial collagen deposition (Ayala et al, 2012). In another in vivo model of cardiac remodeling and fibrosis, it was demonstrated that 4-PBA treatment increased overall survival through the reduction of myocardial infarct induced damage and subsequent cardiac rupture (Luo et al, 2015). This study also provided evidence that 4-PBA can down regulate ER stress factors and decrease the synthesis of pro-fibrotic proteins (Luo et al, 2015).…”

4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress

“…In this study, we shed light on the temporal relationship between ER stress and LVH, demonstrating that the ER stress response persists up to 4 weeks after TAC. Although mechanisms by which ER stress modulates myocardial hypertrophy and interstitial fibrosis remain unclear, some suggest involvement of CaN-MEF2c signaling pathways in cardiomyocytes [7] and TGFβ1-Smad2/3 in cardiac fibroblasts [10]. Further investigations are needed to detail the putative mechanisms.…”

“…The animals were housed in the 12-12 cycle environment, and checked three times each day. The dosage of 4-PBA was determined according to our previous study [10]. At the end of 4 weeks, the surviving animals were subjected to echocardiographic imaging, then euthanized for autopsy, and histological analysis, and western blotting.…”

“…Therefore, inhibiting ER stress may be an important consideration in developing treatments for ischemic or hypertrophic cardiomyopathy. To that effect, our previous study has indicated that attenuation of ER stress by administration of 4-Phenylbutyric acid (4-PBA) at 20 mg/kg/day in a mouse model of myocardial infarction (MI) prevents cardiac rupture and remodeling by inhibiting cardiac apoptotic and fibrotic signal pathways [10]. However, little is known whether the administration of 4-PBA is effective on mitigating hypertrophic heart disease.…”

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…I/R injury rats are accompanied by myocardial infarction (MI), and increased myocardial infarct size and myocardial enzyme activity were observed [106] . Luo et al [110] reported that MI induced ERS and provoked cardiac apoptosis and fibrosis by increasing the expression of ERS markers GRP78 and CHOP, pro-apoptotic proteins Bax and caspase 3, and pro-fibrotic proteins transforming growth factor-beta 1 (TGF-β1) and Smad 2/3, culminating in cardiac rupture and remodeling. Li et al [111] reported that ERS contributed to MI through the activation of NADPH oxidase.…”