Statins activate GATA-6 and induce differentiated vascular smooth muscle cells |
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Authors: | Wada Hiromichi Abe Mitsuru Ono Koh Morimoto Tatsuya Kawamura Teruhisa Takaya Tomohide Satoh Noriko Fujita Masatoshi Kita Toru Shimatsu Akira Hasegawa Koji |
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Affiliation: | a Division of Translational Research, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan b Division of Metabolic Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan c Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan d Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan e Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan |
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Abstract: | The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) beyond cholesterol lowering involve their direct actions on vascular smooth muscle cells (VSMCs). However, the effects of statins on phenotypic modulation of VSMCs are unknown. We herein show that simvastatin (Sm) and atorvastatin (At) inhibited DNA synthesis in human aortic VSMCs dose-dependently, while cell toxicity was not observed below the concentration of 1 μM of Sm or 100 nM of At. Stimulating proliferative VSMCs with Sm or At induced the expression of SM-α-actin and SM-MHC, highly specific markers of differentiated phenotype. Sm up-regulated the binding activity of GATA-6 to SM-MHC GATA site and activated the transfected SM-MHC promoter in proliferative VSMCs, while mutating the GATA-6 binding site abolished this activation. Geranylgeranylpyrophosphate (10 μM), an inhibitor of Rho family proteins, abolished the statin-mediated induction of the differentiated phenotype in VSMCs. These findings suggest that statins activate GATA-6 and induce differentiated VSMCs. |
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Keywords: | Statin GATA-6 Vascular smooth muscle cells Phenotypic modulation |
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