Inhibition of Calpain Alleviates Apoptosis in Coxsackievirus B3-induced Acute Virus Myocarditis Through Suppressing Endoplasmic Reticulum Stress.

Abstract

Virus myocarditis (VMC) is a common cardiovascular disease and a major cause of sudden death in young adults. However, there is still a lack of effective treatments. Our previous studies found that calpain activation was involved in VMC pathogenesis. This study aims to explore the underlying mechanisms further. Neonatal rat cardiomyocytes (NRCMs) and transgenic mice overexpressing calpastatin (Tg-CAST), the endogenous calpain inhibitor, were used to establish VMC model. Hematoxylin and eosin and Masson staining revealed inflammatory cell infiltration and fibrosis. An ELISA array detected myocardial injury. Cardiac function was measured using echocardiography. CVB3 replication was assessed by capsid protein VP1. Apoptosis was measured by TUNEL staining, flow cytometry, and western blot. The endoplasmic reticulum (ER) stress-related proteins were detected by western blot. Our data showed that CVB3 infection resulted in cardiac injury, as evidenced by increased inflammatory responses and fibrosis, which induced myocardial apoptosis. Inhibiting calpain, both by PD150606 and calpastatin overexpression, could attenuate these effects. Furthermore, ER stress was activated during CVB3 infection. However, calpain inhibition could downregulate some ER stress-associated protein levels such as GRP78, pancreatic ER kinase-like ER kinase (PERK), and inositol-requiring enzyme-1α (IRE-1α), and ER stress-related apoptotic factors, during CVB3 infection. In conclusion, calpain inhibition attenuated CVB3-induced myocarditis by suppressing ER stress, thereby inhibiting cardiomyocyte apoptosis.

• Authors: Hui Shi, Ying Yu, Yucheng Wang, Xiaoxiao Liu, Yong Yu, Minghui Li, Yunzeng Zou, Ruizhen Chen, Junbo Ge
• Journal: International heart journal (Int Heart J) Vol. 62 Issue 4 Pg. 900-909 (Jul 30 2021) ISSN: 1349-3299 [Electronic] Japan
• PMID: 34234076 (Publication Type: Journal Article)

Chemical References

• Acrylates
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Hspa5 protein, mouse
• PD 150606
• Calpain

Topics

• Acrylates (pharmacology, therapeutic use)
• Animals
• Animals, Newborn
• Apoptosis (drug effects)
• Calpain (antagonists & inhibitors, metabolism)
• Coxsackievirus Infections (drug therapy, metabolism)
• Drug Evaluation, Preclinical
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Enterovirus B, Human
• Mice, Transgenic
• Myocarditis (drug therapy, metabolism, virology)
• Myocytes, Cardiac (drug effects)
• Rats, Sprague-Dawley