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Statins activate GATA-6 and induce differentiated vascular smooth muscle cells

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 {mu}M of Sm or 100 nM of At. Stimulating proliferative VSMCs with Sm or At induced the expression of SM-{alpha}-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 {mu}M), 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.
Authors:
Wada, Hiromichi; [1]  Abe, Mitsuru; Ono, Koh; [2]  Morimoto, Tatsuya; Kawamura, Teruhisa; Takaya, Tomohide; [1]  Satoh, Noriko; [3]  Fujita, Masatoshi; [4]  Kita, Toru; [2]  Shimatsu, Akira; [5]  Hasegawa, Koji [1] 
  1. Division of Translational Research, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555 (Japan)
  2. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto (Japan)
  3. Division of Metabolic Research, National Hospital Organization Kyoto Medical Center, Kyoto (Japan)
  4. Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto (Japan)
  5. Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto (Japan)
Publication Date:
Oct 03, 2008
Product Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 374; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2008.07.098; PII: S0006-291X(08)01444-7; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Subject:
60 APPLIED LIFE SCIENCES; ACTIN; CHOLESTEROL; COENZYMES; DNA; MUSCLES; PHENOTYPE; PROMOTERS; TOXICITY
OSTI ID:
21143888
Country of Origin:
United States
Language:
English
Other Identifying Numbers:
Journal ID: ISSN 0006-291X; BBRCA9; TRN: US08R2218023801
Availability:
Available from http://dx.doi.org/10.1016/j.bbrc.2008.07.098;INIS
Submitting Site:
INIS
Size:
page(s) 731-736
Announcement Date:
Apr 09, 2009

Citation Formats

Wada, Hiromichi, Abe, Mitsuru, Ono, Koh, Morimoto, Tatsuya, Kawamura, Teruhisa, Takaya, Tomohide, Satoh, Noriko, Fujita, Masatoshi, Kita, Toru, Shimatsu, Akira, and Hasegawa, Koji. Statins activate GATA-6 and induce differentiated vascular smooth muscle cells. United States: N. p., 2008. Web. doi:10.1016/j.bbrc.2008.07.098.
Wada, Hiromichi, Abe, Mitsuru, Ono, Koh, Morimoto, Tatsuya, Kawamura, Teruhisa, Takaya, Tomohide, Satoh, Noriko, Fujita, Masatoshi, Kita, Toru, Shimatsu, Akira, & Hasegawa, Koji. Statins activate GATA-6 and induce differentiated vascular smooth muscle cells. United States. doi:10.1016/j.bbrc.2008.07.098.
Wada, Hiromichi, Abe, Mitsuru, Ono, Koh, Morimoto, Tatsuya, Kawamura, Teruhisa, Takaya, Tomohide, Satoh, Noriko, Fujita, Masatoshi, Kita, Toru, Shimatsu, Akira, and Hasegawa, Koji. 2008. "Statins activate GATA-6 and induce differentiated vascular smooth muscle cells." United States. doi:10.1016/j.bbrc.2008.07.098. https://www.osti.gov/servlets/purl/10.1016/j.bbrc.2008.07.098.
@misc{etde_21143888,
title = {Statins activate GATA-6 and induce differentiated vascular smooth muscle cells}
author = {Wada, Hiromichi, Abe, Mitsuru, Ono, Koh, Morimoto, Tatsuya, Kawamura, Teruhisa, Takaya, Tomohide, Satoh, Noriko, Fujita, Masatoshi, Kita, Toru, Shimatsu, Akira, and Hasegawa, Koji}
abstractNote = {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 {mu}M of Sm or 100 nM of At. Stimulating proliferative VSMCs with Sm or At induced the expression of SM-{alpha}-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 {mu}M), 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.}
doi = {10.1016/j.bbrc.2008.07.098}
journal = {Biochemical and Biophysical Research Communications}
issue = {4}
volume = {374}
place = {United States}
year = {2008}
month = {Oct}
}