CDK9 regulates neointima formation following vascular injury via targeting transcription factor Twist1

Background Restenosis is a major limiting factor of percutaneous coronary intervention (PCI), accompanied by abnormal proliferation, migration and phenotypic switching of vascular smooth muscle cells (VSMCs). As a key component of positive transcription factor-b (P-TEFb), CDK9 phosphorylates RNA polymerase II and regulates various genes that are involved in the regulation of diverse cellular processes including cell growth and proliferation. In this study we investigated whether and how CDK9 regulated vascular remodeling after injury in mice. Results Our study observes a marked upregulation of CDK9 and its substrate pSer2 in VSMCs during neointimal hyperplasia following carotid artery injury, and the neointimal formation can be remarkably ameliorated by the CDK9 inhibitor (iCDK9). Overexpression of CDK9 promotes phenotypic switching, proliferation and migration of VSMCs in vitro, whereas inhibition of CDK9 obtains the opposites results. Moreover, CDK9 upregulates the expression of transcription factor Twist1, which is a key inducer of epithelial-mesenchymal transition (EMT) and has been widely implicated in the pathological progression of cardiovascular diseases. Furthermore, application of the Twist1 inhibitor Harmine largely abolished the function of CDK9 in promoting VSMCs phenotypic switching, proliferation and migration in vitro. Conclusions Our findings demonstrate a crucial regulatory role of CDK9 in neointima formation after vascular injury, and strategies targeting CDK9 inhibition potentially overcome limitations of sustained efficacy following PCI.