Acceleration of Cardiovascular Disease by a Dysfunctional Prostacyclin Receptor Mutation

Abstract

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 (nϭ980), with no association in the low-risk cohort (nϭ2293). 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. [1][2][3][4] and the development of cardiovascular disease in predisposed prostacyclin receptor knockout mice, 5,6 underscores the necessity to better understand the effects of COX-2-derived metabolites on cardiovascular health. Endothelial prostacyclin synthesis requires the COX-2 enzyme 7 and may serve a role in protection from atherothrombosis. 8,9 This cardioprotective role has been supported by recent prostacyclin receptor knockout mice studies showing that the absence of the prostacyclin receptor (IP) (International Union of Pharmacology Receptor classification) leads to intimal hyperplasia, atherosclerosis, and hypercoagulability, 5,6 as well as reperfusion injury, 10 and premenopausal atherogenesis. 11 Despite such accumulating information, controversy remains as to whether prostacyclin deficiency is the etiology of the cardiovascular events observed with COX-2 inhibition, 12 particularly as no human studies have directly implicated defective prostacyclin signaling in the development of cardiovascular disease.The human prostacyclin receptor (hIP) gene (PTGIR) spans approximately 7000 bases along chromosome 19 (locus Original received October 11, 2007; revision received February 12, 2008; accepted February 21, 2008 19q13.3) and is comprised of 3 exons separated by 2 introns, 1 intron...

Regulation of the human prostacyclin receptor gene by the cholesterol-responsive SREBP1

“…Prostacyclin also acts as a critical cardio/cytoprotective agent during acute myocardial ischemia ( 15-17 ) and enhances endothelial cell (EC) survival, supporting neovascularization ( 18 ). Several single-nucleotide polymorphisms occur in the hIP gene that correlate with receptor dysfunction, including enhanced platelet activation in deep vein thrombosis and increased intimal hyperplasia ( 19-21 ) and, more recently, with increased occurrence of major obstruction in patients with coronary artery disease ( 19,22,23 ) …”

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents

“…The exception is performed by the fluorinated series of compounds, whose ethyl ester derivatives seem to be more selective than the bulkier analogues (i-propyl and n-butyl derivatives). Since the hydrolysis of the ester can occur at least to some extent in vivo, ester compounds 26-32 and 59-66 were evaluated in comparison with the corresponding acid (19)(20)(21)(22)(23)(24)(25) [25g]. In general the ester derivatives proved to be more effective and selective toward COX-2 with respect to acid derivatives and only in the case of 3-F phenyl substituted derivatives the acid compound 23 and the esters compounds 30, 61 and 62 displayed closer potencies.…”

“…reduced generation of the second messenger c-AMP after activation of the receptor [22]. Importantly, Arehart et al [22] have shown that patients who were carriers of the SNP R212C were associated with increased cardiovascular disease and events, analogously to COX-2 inhibition.…”

Individual variation of human S1P1 coding sequence leads to heterogeneity in receptor function and drug interactions

“…We also report one mutation that is associated with a signifi cantly higher incidence in the cardiovascular disease cohort. ( 35 ). Genomic DNA was extracted from blood using a PuregeneH system (Gentra Systems).…”