RORα suppresses proliferation of vascular smooth muscle cells through activation of AMP-activated protein kinase

초록

Background: Retinoic acid-related orphan receptor alpha (ROR alpha) has been implicated in the progression of atherosclerosis, but its role in the proliferation of vascular smooth muscle cells (vSMCs) has not been fully examined. We previously reported that ROR alpha activates AMP-activated protein kinase (AMPK), which is associated with the suppression of vSMC proliferation. Therefore, we investigated the suppressive function of ROR alpha on the proliferation of vSMCs and the molecular mechanisms involved. Results: First, ROR alpha and its activator, cholesterol sulfate (CS), induced the activation of AMPK in both human aortic SMCs and rat A7r5 cells, which was accompanied by the suppression of mammalian target of rapamycin (mTOR) and p70 ribosomal protein S6 kinase 1. Second, ROR alpha and CS modulated the expression of cell-cycle-regulating factors, such as p53, p27, and cyclin D in vSMCs. Consistent with this, the overexpression of ROR alpha or CS treatment suppressed the proliferation of human aortic SMCs and rat A7r5 cells, possibly through G(1) arrest. ROR alpha and CS also inhibited the migration of A7r5 cells in two-dimensional and three-dimensional cell migration assays. Finally, we demonstrated that the infusion of adenovirus encoding ROR alpha into arteries suppressed neointima formation after balloon injury in rats. Conclusion: These results demonstrate that ROR alpha inhibits vSMC proliferation through AMPK-induced mTOR suppression, and suggest that ROR alpha is a therapeutic target for the cardiovascular diseases associated with vSMC proliferation. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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