title: Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation: potential implications for cyclooxygenase-2 inhibition.
abstract: 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.
authors.affiliation: Department of Pharmacology & Toxicology, Dartmouth-Hitchcock Medical Center, Hanover, NH 03755, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Arehart
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Stitham
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.forename: Karen
authors.initials: K
authors.lastname: Douville
authors.forename: Todd
authors.initials: T
authors.lastname: MacKenzie
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Fetalvero
authors.forename: Scott
authors.initials: S
authors.lastname: Gleim
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Kasza
authors.forename: Yamini
authors.initials: Y
authors.lastname: Rao
authors.forename: Laurie
authors.initials: L
authors.lastname: Martel
authors.forename: Sharon
authors.initials: S
authors.lastname: Segel
authors.forename: John
authors.initials: J
authors.lastname: Robb
authors.forename: Aaron
authors.initials: A
authors.lastname: Kaplan
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Powell
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Eric B
authors.initials: EB
authors.lastname: Rimm
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Martin
authors.forename: John
authors.initials: J
authors.lastname: Hwa
mesh_terms: D002318:Cardiovascular Diseases / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects*; D018450:Disease Progression; D006801:Humans; D020125:Mutation, Missense; D044006:Receptors, Epoprostenol / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D044006:Receptors, Epoprostenol; D043562:Receptors, G-Protein-Coupled