ADAMTS8 Promotes Cardiac Fibrosis Partly Through Activating EGFR Dependent Pathway

Yafang Zha,Jian Wang,Jiayan Zhang,Song Zhang,Yuheng Jiao,Zhuowang Ge,Yanyan Li

doi:10.3389/fcvm.2022.797137

Abstract

Myocardial infarction or pressure overload leads to cardiac fibrosis, the leading cause of heart failure. ADAMTS8 (A disintegrin and metalloproteinase with thrombospondin motifs 8) has been reported to be involved in many fibrosis-related diseases. However, the specific role of ADAMTS8 in cardiac fibrosis caused by myocardial infarction or pressure overload is yet unclear. The present study aimed to explore the function of ADAMTS8 in cardiac fibrosis and its underlying mechanism. ADAMTS8 expression was significantly increased in patients with dilated cardiomyopathy; its expression myocardial infarction and TAC rat models was also increased, accompanied by increased expression of α-SMA and Collagen1. Adenovirus-mediated overexpression of ADAMTS8 through cardiac in situ injection aggravated cardiac fibrosis and impaired cardiac function in the myocardial infarction rat model. Furthermore, in vitro studies revealed that ADAMTS8 promoted the activation of cardiac fibroblasts; ADAMTS8 acted as a paracrine mediator allowing for cardiomyocytes and fibroblasts to communicate indirectly. Our findings showed that ADAMTS8 could damage the mitochondrial function of cardiac fibroblasts and then activate the PI3K-Akt pathway and MAPK pathways, promoting up-regulation of YAP expression, with EGFR upstream of this pathway. This study systematically revealed the pro-fibrosis effect of ADAMTS8 in cardiac fibrosis and explored its potential role as a therapeutic target for the treatment of cardiac fibrosis and heart failure.

Highlights

Heart failure is an increasingly concerning public health problem with alarming morbidity and mortality, and cardiac fibrosis remains the main pathological outcome of heart failure [1]
We compared ADAMTS8 expression in normal hearts obtained from healthy donors in traffic accidents and failing hearts obtained from patients with dilated cardiomyopathy (DCM) undergoing surgery
The present study has made some major findings that can be outlined as the following: [1] ADAMTS8 expression was increased in the myocardial infarction (MI) rat model, cardiac fibrosis induced by transverse aortic constriction (TAC), and patients with heart failure, which were all accompanied by myofibroblast activation and collagen fiber deposition in these diseases and models

Summary

Introduction

Heart failure is an increasingly concerning public health problem with alarming morbidity and mortality, and cardiac fibrosis remains the main pathological outcome of heart failure [1]. The prominent features of cardiac fibrosis are excessive remodeling and accumulation of extracellular matrix (ECM) [2]. When injury or pressure overload occurs, cardiac fibroblasts differentiate into highly specialized myofibroblasts, increasing the production/secretion of fibrous collagen, stromal cell proteins, and the expression of α-smooth muscle actin (α-SMA, ACTA2 gene) to cope with injury or stress [4]. The development of cardiac fibrosis is controlled by the myocyte-fibroblast communication [5]. Appropriate fibrotic response contributes to tissue repair. Excessive fibrosis caused by continuous activation of myofibroblasts can lead to a gradual decrease in tissue

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