Abstract 1992: Microrna-145 in Vascular Smooth Muscle Cell Biology and Vascular Disease
Vascular smooth muscle cell (VSMC) phenotypic modulation and proliferation plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. Recently, we have found that microRNA-145 (miR-145) is the most abundant miRNA in normal vascular walls and in fresh isolated VSMCs; however, the role of miR-145 in VSMC biology and vascular diseases is currently unknown. Here we find that miR-145 is selectively expressed in VSMCs of the vascular wall and its expression is significantly downregulated in the vascular walls with neointimal lesion formation and in cultured dedifferentiated VSMCs. More importantly, both in cultured rat VSMCs in vitro and in balloon-injured rat carotid arteries in vivo, we demonstrate that the noncoding RNA miR-145 is a novel modulator for VSMC phenotype and proliferation. VSMC differentiation marker genes are upregulated by pre-miR-145 or adenovirus expressing miR-145 (Ad-miR-145), but are downregulated by miR-145 inhibitor, 2′OMe-miR-145. In contrast, VSMC proliferation is inhibited by pre-miR-145 or Ad-miR-145 and increased by 2′OMe-miR-145. We have further identified that miR-145-mediated phenotypic modulation and proliferative change of VSMCs are through its target gene KLF5 and its downstream signaling molecules, myocardin and PCAN. Finally, restoration of miR-145 in balloon-injured arteries via Ad-miR-145 inhibits neointimal growth. We conclude that miR-145 is a novel modulator for VSMC phenotype and proliferation marker that is able of controlling vascular neointimal lesion formation. These novel findings may have extensive implications for the diagnosis and therapy of a variety of proliferative vascular diseases.