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(Circulation Research. 2008;102:986.)
© 2008 American Heart Association, Inc.

Clinical Research

Acceleration of Cardiovascular Disease by a Dysfunctional Prostacyclin Receptor Mutation

Potential Implications for Cyclooxygenase-2 Inhibition

Eric Arehart^*, Jeremiah Stitham^*, Folkert W. Asselbergs^*, Karen Douville, Todd MacKenzie, Kristina M. Fetalvero, Scott Gleim, Zsolt Kasza, Yamini Rao, Laurie Martel, Sharon Segel, John Robb, Aaron Kaplan, Michael Simons, Richard J. Powell, Jason H. Moore, Eric B. Rimm, Kathleen A. Martin, John Hwa

From the Departments of Pharmacology & Toxicology (E.A., J.S., K.D., K.M.F., S.G., Z.K., Y.R., K.A.M., J.H), General Medicine (T.M.), Cardiology (L.M., S.S., J.R., A.K., M.S., J.H.), Vascular Surgery (R.J.P.), and Genetics (J.H.M.), Dartmouth-Hitchcock Medical Center, Lebanon, and Dartmouth Medical School, Hanover, NH; Department of Cardiology (F.W.A.), University Medical Center Groningen, The Netherlands; and Department of Epidemiology and Nutrition (F.W.A., E.B.R.), Harvard School of Public Health, Boston, Mass.

Correspondence to John Hwa, MD, PhD, Department of Pharmacology & Toxicology, Dartmouth Medical School, 7650 Remsen, Hanover, NH 03755. E-mail John.Hwa{at}Dartmouth.edu

Recent increased adverse cardiovascular events observed with selective cyclooxygenase-2 inhibition led to the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra), but the mechanisms underlying these atherothrombotic events remain unclear. Prostacyclin is the major end product of cyclooxygenase-2 in vascular endothelium. Using a naturally occurring mutation in the prostacyclin receptor, we report for the first time that a deficiency in prostacyclin signaling through its G protein–coupled receptor contributes to atherothrombosis in human patients. We report that a prostacyclin receptor variant (R212C) is defective in adenylyl cyclase activation in both patient blood and in an in vitro COS-1 overexpression system. This promotes increased platelet aggregation, a hallmark of atherothrombosis. Our analysis of patients in 3 separate white cohorts reveals that this dysfunctional receptor is not likely an initiating factor in cardiovascular disease but that it accelerates the course of disease in those patients with the greatest risk factors. R212C was associated with cardiovascular disease only in the high cardiovascular risk cohort (n=980), with no association in the low-risk cohort (n=2293). In those at highest cardiovascular risk, both disease severity and adverse cardiovascular events were significantly increased with R212C when compared with age- and risk factor–matched normal allele patients. We conclude that for haploinsufficient mutants, such as the R212C, the enhanced atherothrombotic phenotype is likely dependent on the presence of existing atherosclerosis or injury (high risk factors), analogous to what has been observed in the cyclooxygenase-2 inhibition studies or prostacyclin receptor knockout mice studies. Combining both biochemical and clinical approaches, we conclude that diminished prostacyclin receptor signaling may contribute, in part, to the underlying adverse cardiovascular outcomes observed with cyclooxygenase-2 inhibition.

Key Words: prostacyclin • eicosanoid • cyclooxygenase-2 • G protein coupled receptor • mutation

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