Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation - Potential implications for cyclooxygenase-2 inhibition
Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation - Potential implications for cyclooxygenase-2 inhibition
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DOI：
10.1161/circresaha.107.165936
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发表时间：
2008-04-25
影响因子：
20.1
通讯作者：
Hwa, John
中科院分区：
文献类型：
--
作者：
Arehart, Eric;Stitham, Jeremiah;Hwa, John
最近，通过选择性环氧合酶-2 抑制观察到不良心血管事件增加，导致罗非考昔 (Vioxx) 和伐地考昔 (Bextra) 停药，但这些动脉粥样硬化血栓事件的机制仍不清楚。前列环素是血管内皮细胞中环氧合酶 2 的主要终产物。利用前列环素受体中自然发生的突变，我们首次报告说，通过其 G 蛋白偶联受体的前列环素信号传导缺陷会导致人类患者的动脉粥样硬化血栓形成。我们报告说，前列环素受体变体 (R212C) 在患者血液和体外 COS-1 过表达系统中的腺苷酸环化酶激活方面存在缺陷。这会促进血小板聚集增加，这是动脉粥样硬化血栓形成的标志。我们对 3 个独立白人群体的患者进行的分析表明，这种功能失调的受体不太可能是心血管疾病的起始因素，但它会加速那些具有最大危险因素的患者的病程。 R212C 仅在高心血管风险队列 ( n = 980) 中与心血管疾病相关，而在低风险队列 ( n = 2293) 中没有关联。与年龄和危险因素匹配的正常等位基因患者相比，在心血管风险最高的患者中，R212C 治疗后疾病严重程度和不良心血管事件均显着增加。我们的结论是，对于单倍体不足的突变体，例如 R212C，增强的动脉粥样硬化血栓表型可能取决于现有动脉粥样硬化或损伤（高风险因素）的存在，类似于环加氧酶 2 抑制研究或前列环素受体敲除小鼠研究中观察到的情况。结合生化和临床方法，我们得出结论，前列环素受体信号传导减弱可能部分导致环加氧酶 2 抑制所观察到的潜在不良心血管结局。
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.