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*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    96 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)986-993
    Number of pages8
    JournalCirculation research
    Volume102
    Issue number8
    DOIs
    Publication statusPublished - 25-Apr-2008

    Keywords

    • prostacyclin
    • eicosanoid
    • cyclooxygenase-2
    • G protein coupled receptor
    • mutation
    • SYNTHETIC MUTATIONS
    • COX-2 INHIBITORS
    • HEART-FAILURE
    • MICE LACKING
    • POLYMORPHISM
    • ACTIVATION
    • RHODOPSIN
    • RESIDUES
    • BINDING
    • HELICES

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