Sacubitril/Valsartan Alleviates Experimental Autoimmune Myocarditis by Inhibiting Th17 Cell Differentiation Independently of the NLRP3 Inflammasome Pathway.

Wei Liang,Yu-Hua Liao,Jing Yuan,Xiang Cheng,Min Wang,Bai-Kang Xie,Pei-Wu Ding,Miao Yu

doi:10.3389/fphar.2021.727838

Abstract

Sacubitril/valsartan (Sac/Val) is a recently approved drug that is commonly used for treatment of heart failure. Several studies indicated that Sac/Val also regulated the secretion of inflammatory factors. However, the effect and mechanism of this drug modulation of inflammatory immune responses are uncertain. In this study, an experimental autoimmune myocarditis (EAM) mouse model was established by injection of α-myosin-heavy chain peptides. The effect of oral Sac/Val on EAM was evaluated by histological staining of heart tissues, measurements of cardiac troponin T and inflammatory markers (IL-6 and hsCRP). The effects of Sac/Val on NLRP3 inflammasome activation and Th1/Th17 cell differentiation were also determined. To further explore the signaling pathways, the expressions of cardiac soluble guanylyl cyclase (sGC) and NF-κB p65 were investigated. The results showed that Sac/Val downregulated the inflammatory response and attenuated the severity of EAM, but did not influence NLRP3 inflammasomes activation. Moreover, Sac/Val treatment inhibited cardiac Th17 cell differentiation, and this might be associated with sGC/NF-κB p65 signaling pathway. These findings indicate the potential use of Sac/Val for treatment of myocarditis.

Highlights

Myocarditis is an inflammatory disease of the myocardium whose manifestations range from subclinical disease to heart failure, cardiogenic shock, arrhythmias, and sudden death (Caforio et al, 2013)
Sacubitril/valsartan (Sac/Val) is an angiotensin receptor-neprilysin inhibitor (ARNI) that reduces the risk of death and hospitalization of patients with heart failure, and researches show that it is superior to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) in alleviating heart failure (Lefer and Sharp, 2018; Velazquez et al, 2019)
These results showed that Sac/Val treatment downregulated the expression of inflammatory factors, attenuated the severity of experimental autoimmune myocarditis (EAM)

Summary

Introduction

Myocarditis is an inflammatory disease of the myocardium whose manifestations range from subclinical disease to heart failure, cardiogenic shock, arrhythmias, and sudden death (Caforio et al, 2013). Multiple innate and adaptive immune responses such as activation of NLRP3 inflammasomes and Th1/Th17 cell differentiation occur during myocarditis Sacubitril/valsartan (Sac/Val) is an angiotensin receptor-neprilysin inhibitor (ARNI) that reduces the risk of death and hospitalization of patients with heart failure, and researches show that it is superior to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) in alleviating heart failure (Lefer and Sharp, 2018; Velazquez et al, 2019). Its effect in inflammatory diseases and the mechanism underling its anti-inflammatory pathways are not well understood

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Conclusion