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• W2097319062 abstract "It is becoming increasingly clear that cholesterol-independent effects of statins also contribute to the cardioprotective effects, but these mechanisms remain poorly understood. We investigated the effects of lovastatin on vascular smooth muscle phenotype. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition with rapamycin induces vascular smooth muscle cell (VSMC) differentiation. We found that lovastatin also inhibits mTORC1 signaling and that this inhibition is required for VSMC differentiation. Lovastatin inhibition of mTORC1 was farnesylation dependent, suggesting the farnesylated G protein Rheb (Ras homologue enriched in brain), a known upstream activator of mTORC1. Rheb overexpression induced mTORC1 activity and repressed contractile protein expression, but a farnesylation-deficient mutant (C18S) elicited the opposite effect. Rheb knockdown with small interfering RNA was also sufficient to inhibit mTORC1 and induce contractile protein expression, and it prevented statin-induced VSMC differentiation. Notably, mTORC1 activity was elevated in VSMC isolated from an intimal hyperplastic patient lesion compared with normal media, and lovastatin treatment inhibited mTORC1 activity in these cultures. Furthermore, lovastatin inhibited mTORC1 activity and prevented the downregulation of contractile protein expression in an ex vivo angioplasty model. In conclusion, these findings illustrate a mechanism for the cardioprotective effects of lovastatin through inhibition of Rheb and mTORC1 and promotion of a differentiated VSMC phenotype." @default.
• W2097319062 created "2016-06-24" @default.
• W2097319062 creator A5045547193 @default.
• W2097319062 creator A5045922184 @default.
• W2097319062 creator A5071705476 @default.
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• W2097319062 date "2010-07-01" @default.
• W2097319062 modified "2023-10-17" @default.
• W2097319062 title "Lovastatin induces VSMC differentiation through inhibition of Rheb and mTOR" @default.
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• W2097319062 doi "https://doi.org/10.1152/ajpcell.00429.2009" @default.
• W2097319062 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2904260" @default.
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