Simvastatin Attenuates Cardiac Fibrosis via Regulation of Cardiomyocyte-Derived Exosome Secretion.

Shu-Chi Wang,Chong-Chao Hsieh,Chih-Hsin Hung,Chia-Yuan Chang,Chia-Yang Li,Yu-Ru Liu,Po-Len Liu,Hsuan-Fu Kuo,Po-Lin Kuo

doi:10.3390/jcm8060794

Abstract

Exosome-mediated communication within the cardiac microenvironment is associated with cardiac fibrosis. Simvastatin (SIM), a potent statin, protects against cardiac fibrosis, but its mechanism of action is unclear. We investigated the inhibitory effects and underlying mechanism of simvastatin in cardiac fibrosis, by regulating exosome-mediated communication. Male Sprague-Dawley rats were treated with angiotensin (Ang) II alone, or with SIM for 28 d. Cardiac fibrosis, expressions of fibrosis-associated proteins and mRNAs, and collagen fiber arrangement and deposition were examined. Protein expressions in exosomes isolated from Ang II-treated cardiomyocytes (CMs) were evaluated using nano-ultra-performance liquid chromatographic system, combined with tandem mass spectrometry. Transformation of fibroblasts to myofibroblasts was evaluated using scanning electron and confocal microscopy, and migration assays. Our results showed that SIM attenuated in vivo expression of collagen and collagen-associated protein, as well as collagen deposition, and cardiac fibrosis. The statin also upregulated decorin and downregulated periostin in CM-derived exosomes. Furthermore, it suppressed Ang II-induced transformation of fibroblast to myofibroblast, as well as fibroblast migration. Exosome-mediated cell-cell communication within the cardiac tissue critically regulated cardiac fibrosis. Specifically, SIM regulated the release of CM exosomes, and attenuated Ang II-induced cardiac fibrosis, highlighting its potential as a novel therapy for cardiac fibrosis.

Highlights

Cardiac fibrosis is a common feature of progressive coronary heart disease, and is associated with hypertension, myocardial infarction, cardiomyopathy, and heart failure
The induction of fibrosis was significantly inhibited by SIM treatment
HCF activation and differentiation into myofibroblasts promote cardiac fibrosis progression; the underlying mechanisms of CM-fibroblast communication in cardiac fibrosis and myofibroblast phenotypic expression that are regulated by exosomes remain unclear

Summary

Introduction

Cardiac fibrosis is a common feature of progressive coronary heart disease, and is associated with hypertension, myocardial infarction, cardiomyopathy, and heart failure. A previous study confirmed that cardiac fibrosis played a key role in the progression of heart failure [3]. Communication between myocardial cells and non-CMs plays a key role in maintaining a homeostatic microenvironment and regulating disease progression [5]. Previous studies have revealed that transport of extracellular vesicles between cardiovascular progenitor cells and CMs contributes to improved cardiac function, and attenuates heart failure progression [7]. Mesenchymal stem cell-derived exosomes stimulated CM proliferation and inhibited apoptosis, and aid in transformation of fibroblast to myofibroblast, after induction with transforming growth factor (TGF)-β to enhance cardiac repair [9]. Exosome-mediated cardiac cell communication represents a potential future target for treating or preventing a variety of cardiac diseases, including cardiac fibrosis [10]

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