Gbetagamma-mediated prostacyclin production and cAMP-dependent protein kinase activation by endothelin-1 promotes vascular smooth muscle cell hypertrophy through inhibition of glycogen synthase kinase-3.
Endothelin-1 (ET1) is a vasoactive peptide that stimulates hypertrophy of vascular smooth muscle cells (VSMC) through diverse signaling pathways mediated by G(q)/G(i)/G(13) heterotrimeric G proteins. We have found that ET1 stimulates the activity of cAMP-dependent protein kinase (PKA) in VSMC as profoundly as the G(s)-linked beta-adrenergic agonist, isoproterenol (ISO), but in a transient manner. PKA activation by ET1 was mediated by type-A ET1 receptors (ETA) and recruited an autocrine signaling mechanism distinct from that of ISO, involving G(i)-coupled betagamma subunits of heterotrimeric G proteins, extracellular signal-regulated kinases ERK1/2, cyclooxygenase COX-1 (but not COX-2) and prostacyclin receptors. In the functional studies, inhibition of PKA or COX-1 attenuated ET1-induced VSMC hypertrophy, suggesting the positive role of PKA in this response to ET1. Furthermore, we found that ET1 stimulates a Gbetagamma-mediated, PKA-dependent phosphorylation and inactivation of glycogen synthase kinase-3 (GSK3), an enzyme that regulates cell growth. Together, this study describes that (i) PKA can be transiently activated by G(i)-coupled agonists such as ET1 by an autocrine mechanism involving Gbetagamma/calcium/ERK/COX-1/prostacyclin signaling, and (ii) this PKA activation promotes VSMC hypertrophy, at least in part, through PKA-dependent phosphorylation and inhibition of GSK3.
Taurin
Sebastien
S
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Hogarth
Kyle
K
Sandbo
Nathan
N
Yau
Douglas M
DM
Dulin
Nickolai O
NO
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D011464:Epoprostenol / Q000096:biosynthesis*; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006984:Hypertrophy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007545:Isoproterenol / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D019332:Endothelin-1; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D008565:Membrane Proteins; D014662:Vasoconstrictor Agents; D011464:Epoprostenol; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D007545:Isoproterenol