Salusin-β Promotes Vascular Smooth Muscle Cell Migration and Intimal Hyperplasia after Vascular Injury via ROS/NFκB/MMP-9 Pathway

Aims: Media-to-intima migration of vascular smooth muscle cells (VSMCs) is critical to intimal thickening in atherosclerosis and restenosis after coronary angioplasty. The aim of this study is to determine the effects of salusin-β on VSMC migration and intimal hyperplasia after vascular injury and the underlying mechanism. Results: In vitro, salusin-β promoted VSMC migration, which was attenuated by matrix metalloproteinase (MMP)-9 inhibition. Inhibition or knockdown of p65-nuclear factor kappa beta (NFκB) in VSMCs suppressed salusin-β-induced MMP-9 expression and VSMC migration. Salusin-β increased NADPH oxidase 2 (NOX2) expression and reactive oxygen species (ROS) production, which were prevented by NOX2-small interfering RNA (siRNA) transfection. Salusin-β-induced p65-NFκB translocation, MMP-9 expression, and VSMC migration were inhibited by ROS scavenger, NADPH oxidase inhibitor, or NOX2-siRNA. In vivo, carotid artery ligation-induced vascular injury resulted in intimal hyperplasia in injured artery in rats. Salusin-β was upregulated in the injured carotid arteries of rats, which was attributed to reduced miR-133a-3p expression. Knockdown of salusin-β with siRNA attenuated the vascular injury-induced intimal thickening, p65-NFκB nuclear translocation, and NOX2 and MMP-9 expressions in rats. Innovation: Salusin-β is a critical modulator in VSMC migration and neointima formation in response to vascular injury. Conclusions: Salusin-β promotes VSMC migration and vascular injury-induced intimal hyperplasia via MMP-9 accumulation due to NOX2 activation, followed by ROS production, IκBα phosphorylation and degradation, and p65-NFκB translocation. We propose that salusin-β may be important in the VSMC migration and neointima of some vascular diseases.