3-Hydroxy-3-methylglutaryl CoA reductase inhibitors up-regulate transforming growth factor-β signaling in cultured heart cells via inhibition of geranylgeranylation of RhoA GTPase

Abstract

Transforming growth factor-␤ (TGF␤) signaling has been shown to play a role in cardiac development as well as in the pathogenesis of cardiovascular disease. Prior studies have suggested a relationship between cholesterol metabolism and TGF␤ signaling. Here we demonstrate that induction of the cholesterol metabolic pathway by growth of embryonic chicken atrial cells in medium supplemented with lipoprotein-depleted serum coordinately decreased the expression of the TGF␤ type II receptor (TGF␤RII), TGF␤ 1 , and TGF␤ signaling as measured by plasminogen activator inhibitor-1 (PAI-1) promoter activity. Inhibition of the cholesterol metabolic pathway by the hydrophobic 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase inhibitors, simvastatin and atorvastatin, reversed the effect of lipoproteindepleted serum and up-regulated TGF␤RII expression, whereas the hydrophilic HMGCoA reductase inhibitor, pravastatin, had no effect. Simvastatin stimulated the expression of TGF␤RII, TGF␤ 1 , and PAI-1 at the level of transcription. Experiments using specific inhibitors of different branches of the cholesterol metabolic pathway demonstrated that simvastatin exerted its effect on TGF␤ signaling by inhibition of the geranylgeranylation pathway. C3 exotoxin, which specifically inactivates geranylgeranylated Rho GTPases, mimicked the effect of simvastatin on PAI-1 promoter activity. Cotransfection of cells with a PAI-1 promoter-reporter and a dominantnegative RhoA mutant increased PAI-1 promoter activity, whereas cotransfection with a dominant-active RhoA mutant decreased PAI-1 promoter activity. These data support the conclusion that TGF␤ signaling is regulated by RhoA GTPase and demonstrate a relationship between cholesterol metabolism and TGF␤ signaling. Our data suggest that in patients treated with HMGCoA reductase inhibitors, these agents may exert effects independent of cholesterol lowering on TGF␤ signaling in the heart.Transforming growth factor-␤ (TGF␤) signaling plays an important role in cardiac development, cardiac hypertrophy, ventricular remodeling, and the early response to myocardial infarction (1-2). Data that correlate severe coronary artery disease with levels of circulating activated TGF␤ suggest that TGF␤ signaling might also play a role in atherogenesis (3-5). Studies that demonstrate that TGF␤ is capable of regulating the expression of low-density lipoprotein (LDL) receptors and the incorporation of 14 C-acetate into cholesterol suggest that TGF␤ signaling might play a role in regulating cholesterol metabolism (6, 7). Furthermore, in aortas of cholesterol-fed Watanabe rabbits, levels of TGF␤ 1 are increased (8). These data suggest a relationship between cholesterol metabolism, TGF␤ signaling, and cardiovascular disease.The cholesterol metabolic pathway may be stimulated by depriving cells of lipoproteins and inhibited by 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase inhibitors (9). Farnesylpyrophosphate (FPP) represents a branchpoint in the cholesterol metabolic pathway. Not only does it serve as a ...

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