Activation of ET/ETR axis in myocardial tissue characterizes heart failure induced by experimental autoimmune myocarditis

Abstract

Abstract Background: Endothelial dysfunction is characterized by an imbalance between endothelium-derived vasodilatory and vasoconstrictive effects and may play an important role in the development of heart failure. More and more studies have shown that endothelial-derived NO-mediated vasodilation is attenuated in heart failure patients. However, the role of ET-1 and its receptors in heart failure remains controversial. The aim of this study is to determine whether ET-1 and its receptor are activated in myocarditis and heart failure, and to explore the role of ET-1/ETR in heart failure. Methods: HE staining was used to detect myocardial inflammatory infiltration and myocarditis score, echocardiography to evaluate cardiac function, ELISA to detect serum ET-1 level, and immunohistochemistry and western blot to detect ETAR and ETBR expression in myocardial tissue of rats with myocarditis heart failure. Results: PCM-induced EAM rats tended to reach peak inflammation after 3 weeks of immunization and develop stable chronic HF at week 8 of immunization. Echocardiography was performed on day 21 and 56 of PCM-immunized rats, LVEDd and LVEDs were significantly increased in the EAM group compared to the control group at 3 weeks and 8 weeks while EF and FS were significantly reduced. Therefore, autoimmune myocarditis can induce both acute and chronic heart failure through a PCM-induced autoimmune myocarditis model. Moreover, HE staining revealed that inflammation persisted in EAM-induced acute and chronic heart failure. Serum ET-1 level detected by ELISA method was significantly increased. And immunohistochemistry and western blot indicated that ETAR, and ETBR protein expression in myocardial tissue were significantly elevated in acute heart failure and chronic heart failure. Conclusions: The ET-1/ETR axis were activated in both EAM-induced acute heart failure and chronic heart failure. The ET-1/ETR axis were positively correlated with heart failure and can be used as biomarkers to characterize heart failure.