Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene.

Shengqi Huo,Chenglong Li,Cuntai Zhang,Li Lin,Haiyan Ma,Pengcheng Luo,Sheng Li,Jiayuh Lin,Dan Yan,Junyi Guo,Jiagao Lv,Wei Shi,Hao Zhou

doi:10.1155/2021/6699054

Abstract

Background Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6, respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.

Highlights

Heart failure (HF) is suffered by 26 million people, and the prevalence was approximately 1-2% worldwide as estimated [1]
Our results indicated inhibition of the IL-6/gp130/STAT3 pathway accompanied with the alleviation of the pathological remodeling and heart failure induced by pressure overload; we thought that the intervention of IL-6/STAT3 signal by raloxifene might involve the pivotal mechanism of the remission
We further found that the phosphorylation of STAT3 in the myocardial tissue of Transverse aortic constriction (TAC) mice was significantly increased and IL-6/gp130/STAT3 inhibition has a cardioprotective effect, all of which indicated that the inflammatory signaling pathway of the IL-6/gp130/STAT3 axis might play a crucial role in the cardiac remodeling and heart failure (HF)

Summary

Introduction

Heart failure (HF) is suffered by 26 million people, and the prevalence was approximately 1-2% worldwide as estimated [1]. Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. IL-6/gp130/STAT3 inhibition by raloxifene alleviated TACinduced myocardial inflammation, cardiac remodeling, and dysfunction. Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF

Methods

Results

Discussion

Conclusion