Myostatin mediates abdominal aortic atherosclerosis progression by inducing vascular smooth muscle cell dysfunction and monocyte recruitment

D Verzola,F Montecucco,C Barisione,M Balbi,S Garibaldi,P Ameri,G Garibotto,J H Lindeman,C Brunelli,M Bertolotto,G Ghigliotti,B Villaggio,D Palombo,S Milanesi

doi:10.1038/srep46362

Abstract

Myostatin (Mstn) is a skeletal muscle growth inhibitor involved in metabolic disorders and heart fibrosis. In this study we sought to verify whether Mstn is also operative in atherosclerosis of abdominal aorta. In human specimens, Mstn expression was almost absent in normal vessels, became detectable in the media of non-progressive lesions and increased with the severity of the damage. In progressive atherosclerotic lesions, Mstn was present in the media, neointima, plaque shoulder and in infiltrating macrophages. Mstn co-localized with α-smooth muscle actin (α-SMA) staining and with some CD45+ cells, indicating Mstn expression in VSMCs and bloodstream-derived leukocytes. In vitro, Mstn was tested in VSMCs and monocytes. In A7r5 VSMCs, Mstn downregulated proliferation and Smoothelin mRNA, induced cytoskeletal rearrangement, increased migratory rate and MCP-1/CCR2 expression. In monocytes (THP-1 cells and human monocytes), Mstn acted as a chemoattractant and increased the MCP-1-dependent chemotaxis, F-actin, α-SMA, MCP-1 and CCR2 expression; in turn, MCP-1 increased Mstn mRNA. Mstn induced JNK phosphorylation both in VSMCs and monocytes. Our results indicate that Mstn is overexpressed in abdominal aortic wall deterioration, affects VSMCs and monocyte biology and sustains a chronic inflammatory milieu. These findings propose to consider Mstn as a new playmaker in atherosclerosis progression.

Highlights

The atherosclerotic process is a chronic inflammatory condition that occurs principally in large and medium-sized elastic and muscular arteries
Mstn expression was evaluated by immunohistochemistry in human peri-renal aortic specimens including normal aortae, aortae with non-progressive intimal lesions and aortae with progressive atherosclerotic lesions, up to the stage of fibrotic calcified plaques (FCP), as referred by Van Dijk et al.[26]
In pathological intimal thickening (PIT) and early fibroatheroma (EFA), it diffused from the media to the intimal-medial border zone

Summary

Introduction

The atherosclerotic process is a chronic inflammatory condition that occurs principally in large and medium-sized elastic and muscular arteries. A local co-expression of characteristic protein markers of contractile (Smoothelin, SM22 alpha) and secretory (Collagen 1) phenotypes has been observed in VSMCs from Marfan patients and has been linked to the dysregulation of the transforming growth factor (TGF)-βsystem[9] These findings reveal how the modulation of the VSMC phenotype is a complex, multifaceted process resulting from the interaction of several cellular pathways and extracellular signals. The exposure of aortic endothelial cells to Mstn leads to activation of TGF-βsignaling, decrease of the endothelial NO synthase (eNOS) phosphorylation and increased expression of pro-atherogenic adhesion molecules ICAM-1 and VCAM-123 These findings suggest that the components of vessel wall are direct targets of Mstn, and that Mstn may be relevant for diet-induced metabolic disorders[25]

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Conclusion