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J. Biol. Chem., Vol. 282, Issue 27, 19518-19525, July 6, 2007

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Gβ-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^*

From the Department of Medicine, University of Chicago, Chicago, Illinois 60637

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/G₁₃ 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 β-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 β 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 Gβ-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 Gβ/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.

Received for publication, March 28, 2007 , and in revised form, May 11, 2007.

^* This study was supported by National Institutes of Health Grant HL071755 (to N. O. D.), American Heart Association Grant AHA0235405Z (to N. O. D.), American Heart Association postdoctoral fellowship awards (to S. T. and N. S.), and GlaxoSmithKline pulmonary fellowship award (to K. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Chicago Dept. of Medicine, 5841 S. Maryland Ave., MC 6076, Chicago, IL 60637. Tel.: 773-702-5198; E-mail: ndulin{at}medicine.bsd.uchicago.edu.

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