Chebulinic acid inhibits smooth muscle cell migration by suppressing PDGF-R\u03b2 phosphorylation and inhibiting matrix metalloproteinase-2 expression

In-Sung Song,Sungbo Shim,Sung-Wuk Jang,Jung-Hyun Park,Yu Jeong Jeong

doi:10.1038/s41598-017-12221-w

In-Sung Song, Sungbo Shim + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-12221-w

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Abstract

Excessive migration of vascular smooth muscle cells (VSMCs) after vascular injury contributes to the development of occlusive vascular disease. Inhibition of VSMC migration is a validated therapeutic modality for occlusive vascular diseases, such as atherosclerosis and restenosis. We investigated the inhibitory effect of chebulinic acid (CBA) on cell migration and matrix metalloproteinase (MMP)-2 activation in platelet-derived growth factor (PDGF)-BB-induced mouse and human VSMCs. CBA significantly inhibited PDGF-BB-induced migration in mouse and human VSMCs, without inducing cell death. Additionally, CBA significantly blocked PDGF-BB-induced phosphorylation of the PDGF receptor (PDGF-R), Akt, and extracellular signal-regulated kinase (ERK)1/2 by inhibiting the activation of the PDGF-BB signalling pathway. In both mouse and human VSMCs, CBA inhibited PDGF-induced MMP-2 mRNA and protein expression as well as the proteolytic activity of MMP-2. Moreover, CBA suppressed sprout outgrowth formation of VSMCs from endothelium-removed aortic rings as well as neointima formation following rat carotid balloon injury. Taken together, our findings indicated that CBA inhibits VSMC migration by decreasing MMP-2 expression through PDGF-R and the ERK1/2 and Akt pathways. Our data may improve the understanding of the antiatherogenic effects of CBA in VSMCs.

Highlights

Atherosclerosis is a blood vessel disorder in which arteries thicken because of the accumulation of cholesterol, lipids, vascular smooth muscle cells (VSMCs) and immune cells[1,2,3]
Because platelet-derived growth factor (PDGF)-induced proliferation of VSMCs is critical in atherosclerotic lesion formation and post-angioplasty restenosis[10], we first determined the effect of chebulinic acid (CBA) on PDGF-BB-induced proliferation of mouse aortic SMCs (MOVAS-1 cells) and human aortic SMCs (HASMCs)
When the amount of the newly synthesised DNA was quantified by measuring incorporated 5-bromo-2′-deoxyuridine (BrdU) in HASMCs and MOVAS-1 cells treated with PDGF and CBA for 24 h, CBA did not affect PDGF-induced DNA synthesis (Fig. 1c)

Summary

Introduction

Atherosclerosis is a blood vessel disorder in which arteries thicken because of the accumulation of cholesterol, lipids, vascular smooth muscle cells (VSMCs) and immune cells[1,2,3]. We investigated the inhibitory effect of CBA on PDGF-BB-induced VSMC migration and the potential mechanisms involved using in vitro and in vivo experiments. To investigate the effect of CBA on VSMC migration, we conducted a wound-healing assay using both HASMC and MOVAS-1 cells.

Results

Conclusion