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.

Abstract

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.

• Authors: Sebastien Taurin, Kyle Hogarth, Nathan Sandbo, Douglas M Yau, Nickolai O Dulin
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 27 Pg. 19518-25 (Jul 06 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17513863 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Agonists
• Endothelin-1
• GTP-Binding Protein beta Subunits
• GTP-Binding Protein gamma Subunits
• Membrane Proteins
• Vasoconstrictor Agents
• Epoprostenol
• Cyclooxygenase 1
• Ptgs1 protein, rat
• Cyclic AMP-Dependent Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Glycogen Synthase Kinase 3
• Isoproterenol

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Autocrine Communication (drug effects, genetics)
• Cyclic AMP-Dependent Protein Kinases (genetics, metabolism)
• Cyclooxygenase 1 (genetics, metabolism)
• Endothelin-1 (metabolism, pharmacology)
• Enzyme Activation (drug effects, genetics)
• Epoprostenol (biosynthesis)
• GTP-Binding Protein beta Subunits (genetics, metabolism)
• GTP-Binding Protein gamma Subunits (genetics, metabolism)
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Hypertrophy (enzymology, genetics, pathology)
• Isoproterenol (pharmacology)
• Membrane Proteins (genetics, metabolism)
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Muscle, Smooth, Vascular (cytology, enzymology)
• Myocytes, Smooth Muscle (enzymology, pathology)
• Phosphorylation (drug effects)
• Rats
• Rats, Inbred WKY
• Signal Transduction (drug effects, genetics)
• Vasoconstrictor Agents (metabolism, pharmacology)