Small molecule-mediated induction of miR-9 suppressed vascular smooth muscle cell proliferation and neointima formation after balloon injury

// Onju Ham 1 , Se-Yeon Lee 1 , Byeong-Wook Song 2 , Chang Youn Lee 3 , Jiyun Lee 1 , Hyang-Hee Seo 1 , Sang Woo Kim 4 , Soyeon Lim 3 , Il-Kwon Kim 4 , Seahyoung Lee 4 and Ki-Chul Hwang 4 1 Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea 2 EIT/LOFUS R&D Center, International St. Mary’s Hospital, Incheon, Republic of Korea 3 Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul, Republic of Korea 4 Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Incheon, Republic of Korea Correspondence to: Seahyoung Lee, email: // Ki-Chul Hwang, email: // Keywords : miR-9, PDGFR, small molecule, neointima, Pathology Section Received : March 08, 2017 Accepted : September 04, 2017 Published : September 28, 2017 Abstract Pathologic proliferation and migration of vascular smooth muscle cells (VSMCs) exacerbate cardiovascular disease. MicroRNAs (miRNAs), as endogenous inhibitors of protein synthesis, are expected to modulate pathologic proliferation of VSMCs. Here we report that both platelet-derived growth factor receptor (PDGFR) targeting miR-9 and a small molecule that increases miR-9 can inhibit the serum-induced proliferation of VSMCs. First, based on miRNA-target prediction databases and empirical data, we have selected miR-9 as a potent anti-proliferative miRNA in VSMCs. Further examination indicated that miR-9 directly targets PDGFR disrupting downstream signaling cascades, and this resulted in inhibition of VSMC proliferation and migration. Exogenous delivery of miR-9 inhibited VSMC proliferation in vitro, and a small molecule that increased miR-9 expression also inhibited neointima formation following balloon injury in vivo . We provide evidence of miRNA-mediated modulation of VSMC proliferation and further demonstrate that small molecule-mediated regulation of miRNA targeting a key regulator of VSMC proliferation is a viable therapeutic strategy for treating vascular disease involving pathologic VSMC proliferation such as restenosis.