TY - JOUR
T1 - Suppression of Gαs synthesis by simvastatin treatment of vascular endothelial cells
AU - Kou, Ruqin
AU - Shiroto, Takashi
AU - Sartoretto, Juliano L.
AU - Michel, Thomas
PY - 2012/1/20
Y1 - 2012/1/20
N2 - 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 Gαs abundance, without affecting other Gα subunits. Simvastatin treatment does not influence Gαs protein stability, and paradoxically increases the abundance of Gαs mRNA. Finally, we found that simvastatin treatment inhibits Gαs 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.
AB - 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 Gαs abundance, without affecting other Gα subunits. Simvastatin treatment does not influence Gαs protein stability, and paradoxically increases the abundance of Gαs mRNA. Finally, we found that simvastatin treatment inhibits Gαs 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.
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U2 - 10.1074/jbc.M111.303594
DO - 10.1074/jbc.M111.303594
M3 - Article
C2 - 22144680
AN - SCOPUS:84856078015
VL - 287
SP - 2643
EP - 2651
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 4
ER -