Statins activate GATA-6 and induce differentiated vascular smooth muscle cells.
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 microM 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 microM), 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.
Wada
Hiromichi
H
Division of Translational Research, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan.
Abe
Mitsuru
M
Ono
Koh
K
Morimoto
Tatsuya
T
Kawamura
Teruhisa
T
Takaya
Tomohide
T
Satoh
Noriko
N
Fujita
Masatoshi
M
Kita
Toru
T
Shimatsu
Akira
A
Hasegawa
Koji
K
D000199:Actins / Q000378:metabolism; D020816:Amino Acid Motifs; D000069059:Atorvastatin; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology; D050993:GATA6 Transcription Factor / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D000199:Actins; D004224:Diterpenes; D050993:GATA6 Transcription Factor; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D000069059:Atorvastatin; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate