Activated CD4+ T cells-derived exosomal miR-142-3p boosts post-ischemic ventricular remodeling by activating myofibroblast.

Lidong Cai,Songwen Chen,Xiaofeng Lu,Jun Li,Fangfang Li,Gong Chao,Weifeng Li,Xiaoyu Wu,Genqing Zhou,Guangjian Fan,Yong Wei,Juan Xu,Baozhen Qi,Shaowen Liu,Jumo Zhu

doi:10.18632/aging.103084

Abstract

Cardiac fibrosis is a primary phenotype of cardiac remodeling that contributes to cardiac dysfunction and heart failure. The expansion and activation of CD4+ T cells in the heart has been identified to facilitate pathological cardiac remodeling and dysfunction; however, the underlying mechanisms remained not well clarified. Herein, we found that exosomes derived from activated CD4+ T cells (CD4-activated Exos) evoked pro-fibrotic effects of cardiac fibroblasts, and their delivery into the heart aggravated cardiac fibrosis and dysfunction post-infarction. Mechanistically, miR-142-3p that was enriched in CD4-activated Exos recapitulated the pro-fibrotic effects of CD4-activated Exos in cardiac fibroblasts, and vice versa. Furthermore, miR-142-3p directly targeted and inhibited the expression of Adenomatous Polyposis Coli (APC), a negative WNT signaling pathway regulator, contributing to the activation of WNT signaling pathway and cardiac fibroblast activation. Thus, CD4-activated Exos promote post-ischemic cardiac fibrosis through exosomal miR-142-3p-WNT signaling cascade-mediated activation of myofibroblasts. Targeting miR-142-3p in CD4-activated Exos may hold promise for treating cardiac remodeling post-MI.

Highlights

Myocardial infarction (MI) represents a serious cardiovascular event, and accounts for a leading cause of morbidity and mortality worldwide [1]
Exosomes derived from activated CD4+ T cells promote cardiac fibroblasts activation
As CD4+ T cells infiltration and activation in the heart have been proven to worsen the development of non-infectious myocardial diseases [7, 8]. we wondered that whether exosomes derived from activated CD4+ cells (Exosactivated) contribute to cardiac remodeling post-MI

Summary

Introduction

Myocardial infarction (MI) represents a serious cardiovascular event, and accounts for a leading cause of morbidity and mortality worldwide [1]. Immune therapeutics targeting CD4+ T cells protect the ischemic heart against fibrotic pathology and dysfunction [8]. The deleterious effects of cardiac infiltration of CD4+ T cells have been witnessed in pressure overload-induced cardiac hypertrophy and fibrosis, which could be depressed by genetic inactivation of CD4+ T cells [9]. These findings highlight the contributions of cardiac activated CD4+ T cells to maladaptive cardiac remodeling, but the underlying mediators await further elucidation

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Results

Conclusion