Lovastatin induces VSMC differentiation through inhibition of Rheb and mTOR.
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.
Wagner
Robert J
RJ
Section of Vascular Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
Martin
Kathleen A
KA
Powell
Richard J
RJ
Rzucidlo
Eva M
EM
D000800:Angioplasty, Balloon; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003285:Contractile Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017368:Protein Prenylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011506:Proteins; D034622:RNA Interference; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D002317:Cardiovascular Agents; D003285:Contractile Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D047428:Protein Kinase Inhibitors; D011506:Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D014157:Transcription Factors; D008148:Lovastatin; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins