Inhibition Of Endoplasmic Reticulum Stress Prevents Cardiac Rupture And Attenuates Cardiac Remodeling By Alleviating Mitochondrial Apoptosis And Nlrp3 Inflammasome Activation

Background: Endoplasmic reticulum (ER) stress is involved in myocardial ischemia, but its role and underlying mechanism in the pathogenesis of post-infarct cardiac rupture and remodeling remain unclear. It is known that mitochondrial apoptosis and NLRP3 inflammasome activation are associated with tissue necrosis and fibrosis, which are crucial for cardiac rupture and remodeling. Here we hypothesized that ER stress promotes cardiac rupture and remodeling by increasing mitochondrial apoptosis and NLRP3 inflammation activation. Methods and Results: Left coronary ligation was used to produce myocardial infarction (MI) in C57BL/6 mice. There was 37.5% cardiac rupture rate in the control group during the early phase of MI (2-7 days). The survivals underwent cardiac remodeling and formed ventricular aneurysm with impaired systolic and diastolic functions at the end of 4 weeks. The rupture rate was significantly decreased to 20% in the 4-PBA intraperitoneal injection group (20 mg/kg/day) and the heart functions were improved at the end of 4 weeks. Furthermore, the ventricular aneurysm and myocardial fibrosis were much smaller. Western blot showed that the ER stress markers, mitochondrial bax, caspase 3, NLRP3, TGFβ1 and Smad 2 in the heart tissues of control group were significantly increased after MI, in which mitochondrial bax and caspase 3 were increased markedly in the early phase of MI (3 days), while NLRP3, TGFβ1 and Smad 2 were increased obviously in the late phase of MI (3-28 days). 4-PBA decreased those protein levels in the early and late phases of MI respectively. Then ER stress was induced in neonatal rat’s cardiomyocytes and fibroblasts by 3% hypoxia stimulation for 3 days. Calcein plus CoCL 2 , flow cytometry for JC-1 and western blot for mitochondrial bax and caspase 3 indicated that 4-PBA (0.5 mM) pretreatment protects the cardiomyocytes against mitochondrial-dependent apoptosis induced by hypoxia. Meanwhile, western blot showed that the expression of NLRP3, TGFβ1 and Smad 2 in the fibroblasts were increased by hypoxia stimulation but decreased by 4-PBA. Conclusion: Inhibition of ER stress is a novel therapeutic strategy for preventing post-infarct cardiac rupture and attenuating cardiac remodeling.