The Role And Mechanism Of ER Stress In CVB3-induced Myocarditis

Viral myocarditis (viral myocarditis, VMC) is a clinical necrosis and interstitial inflammatory changes of common cardiovascular diseases caused by viral infection of cardiomyocytes. Coxsackie virus, ECHO, poliovirus, adenovirus40,41, influenza virus infections can cause myocarditis, enteroviruses, especially coxsackievirus B3type (CVB3) is the most common prevalence of viral infection. In viral infection epidemic, acute viral myocarditis may progress to dilated cardiomyopathy or congestive heart failure, the condition can only be alleviated by a heart transplant, there is no effective treatment strategies curing viral myocarditis. In recent years, the incidence in our country and occident with acute viral myocarditis is showing upward trend, and the disease becomes one of the main reasons of unexplained sudden death in young people, which is a serious threat to human health. Currently, the mechanism of viral myocarditis is not fully understood. Numerous studies show that the virus directly destruction of myocardial cells and the overwhelming immune response co-led the development and progression of viral myocarditis,, the overwhelming immune response is the major cause of disease.Endoplasmic reticulum stress (ER stress) is a reaction of the endoplasmic reticulum to sustain cell homeostasisis with the conditions of aberrant glycosylation reaction,calcium homeostasis and accumulation of unfolded proteins. Endoplasmic reticulum stress activates three major signaling pathways, including unfolded protein response (UPR),endoplasmic reticulum-overload response (EOR) and sterol regulatory cascade. Among them, the largest and most thorough studies are focusing on UPR pathway, UPR has three downstream pathways, including ATF6, IRE1and PERK pathway. More and more studies show that ER stress can lead to the occurrence of an immune response to the corresponding control and repair of tissue damage, but under certain conditions, ER stress-induced immune response can lead to too strong histopathological changes to accelerate or lead to diseases such as diabetes, obesity, atherosclerosis and cancer dynamics.Virus infection can also induce ER stress, viral infection causes increased load of endoplasmic reticulum protein folding, over the normal processing capacity, which will lead to accumulation of unfolded protein within the lumen of the endoplasmic reticulum, leading to the occurrence of ER stress. Studies have shown that CVB3can cause ER stress in vitro experiment, but a few articles reported the role of ER stress in heart diseases, and our study was to investigate the role and mechanism of ER stress in CVB3-induced viral myocarditis.In this study, BALB/c mice were infected with CVB3, it was showed that the gene expression level of ER stress senors Grp94and Grp78is significantly higher than non-infected group, and gradually increased with the course of the disease development, and at the same time the results was consistent with the pathology of inflammatory lesions display, in addition, we found that inactivated virus can hardly cause differences of Grp74and Grp94gene expression levels, these results suggested that viral infection can cause myocardial ER stress Then ER stress inducer tunicamycin (Tm) and inhibitor tauroursodeoxycholic acid (TUDCA) were used, Tm treatment can aggravate the disease of CVB3-induced mice, and TUDCA treatment can significantly relieve symptom. Further validate the role of ER stress in the viral myocarditis, then we found that ER stress aggravated myocarditis mainly through the promotion of the inflammatory response by detecting the expression of associated inflammaory factors. Finally, we studied the mechanism, studies have shown that ER stress mainly activated IRE1pathway of UPR, and then IRE1-TRAF2complexes was formed, activating downstream NF-κB pathway mediated immune response. Meanwhile, the use of IRE1inhibitor Irestain9389can significantly alleviate the incidence symptom of myocarditis.Taking these findings, we concluded that CVB3infection can cause ER-stress, and ER-stress promoted the expression of inflammatory factors primarily via IRE1mediated NF-κB pathway, thereby increasing viral myocarditis. Our study revealed the possible mechanism of ER stress involved in viral myocarditis and provided clues and ideas on treatment strategies of the cardiac diseases and viral diseases.