Protective Role of RNA Helicase DEAD-Box Protein 5 in Smooth Muscle Cell Proliferation and Vascular Remodeling.

RATIONALE: RNA helicases, highly conserved enzymes, are currently believed to be not only involved in RNA modulation, but also in other biological processes. We recently reported that RNA helicase DEAD-box protein 5 (DDX5) is required for maintaining the homeostasis of vascular smooth muscle cells (SMCs). However, the expression and function of RNA helicase in vascular physiology and disease is unknown.

OBJECTIVE: To investigate the role of RNA helicase in vascular diseases.

METHODS AND RESULTS: We showed here that DDX5 was the most abundant DEAD-box protein expressed in human and rodent artery, which mainly located in SMCs. It was demonstrated that DDX5 levels were reduced in cytokine-stimulated SMCs and vascular lesions. DDX5 knocking down or deficiency increased SMC proliferation and migration, while overexpression of DDX5 prevented aberrant proliferation and migration of SMCs. Mechanistic studies revealed transcription factor GATA binding protein 6 (GATA-6) as a novel downstream target of DDX5, which directly interacted with GATA-6 and protected it from mouse double minute 2-mediated degradation. Our ChIP assay identified a previously unreported binding of p27Kip1 promoter to GATA-6. DDX5 increased the recruitment of GATA-6 to p27Kip1 promoter, which enhanced p27Kip1 expression and maintained SMC quiescence. Finally, we showed exacerbated neointima formation in DDX5 SMC-deficient mice after femoral artery injury, whereas overexpression of DDX5 potently inhibited vascular remodeling in balloon injured rat carotid artery.

CONCLUSIONS: These findings provide the first evidence for a role of RNA helicase DDX5 in the protection against SMC proliferation, migration, and neointimal hyperplasia. Our data extend the fundamental role of RNA helicase beyond RNA modulation, which provides the basic information for new therapeutic strategies for vascular diseases.