title: Suppression of Gαs synthesis by simvastatin treatment of vascular endothelial cells.
abstract: These studies explore the effects of statins on cyclic AMP-modulated signaling pathways in vascular endothelial cells. We previously observed (Kou, R., Sartoretto, J., and Michel, T. (2009) J. Biol. Chem. 284, 14734-14743) that simvastatin treatment of endothelial cells leads to a marked decrease in PKA-modulated phosphorylation of the protein VASP. Here we show that long-term treatment of mice with simvastatin attenuates the vasorelaxation response to the β-adrenergic agonist isoproterenol, without affecting endothelin-induced vasoconstriction or carbachol-induced vasorelaxation. We found that statin treatment of endothelial cells dose-dependently inhibits PKA activation as assessed by analyses of serine 157 VASP phosphorylation as well as Epac-mediated Rap1 activation. These effects of simvastatin are completely reversed by mevalonate and by geranylgeranyl pyrophosphate, implicating geranylgeranylation as a critical determinant of the stain response. We used biochemical approaches as well as fluorescence resonance energy transfer (FRET) methods with a cAMP biosensor to show that simvastatin treatment of endothelial cells markedly inhibits cAMP accumulation in response to epinephrine. Importantly, simvastatin treatment significantly decreases Gα(s) abundance, without affecting other Gα subunits. Simvastatin treatment does not influence Gα(s) protein stability, and paradoxically increases the abundance of Gα(s) mRNA. Finally, we found that simvastatin treatment inhibits Gα(s) translation mediated by Akt/mTOR/eIF4/4EBP. Taken together, these findings establish a novel mechanism by which simvastatin modulates β-adrenergic signaling in vascular wall, and may have implications for cardiovascular therapeutics.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ruqin
authors.initials: R
authors.lastname: Kou
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiroto
authors.forename: Juliano L
authors.initials: JL
authors.lastname: Sartoretto
authors.forename: Thomas
authors.initials: T
authors.lastname: Michel
mesh_terms: D000818:Animals; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004795:Enzyme Stability; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D000242:Cyclic AMP; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases