Dysfunctional nitric oxide signalling increases risk of myocardial infarction
Dysfunctional nitric oxide signalling increases risk of myocardial infarction
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DOI：
10.1038/nature12722
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发表时间：
2013-12-19
期刊：
影响因子：
64.8
通讯作者：
Schunkert, Heribert
中科院分区：
文献类型：
--
作者：
Erdmann, Jeanette;Stark, Klaus;Schunkert, Heribert
心肌梗死是西方世界的主要死亡原因(1)，通常发生在冠状动脉粥样硬化斑块上的纤维帽破裂时。由此导致的血液暴露于动脉粥样硬化物质，然后引发血栓形成，阻塞动脉(2)。遗传易感性对冠状动脉疾病和心肌梗死的重要性最好的证明是阳性家族史的预测价值(3)。有几个受影响个体的家庭的下一代测序已经彻底改变了突变鉴定(4)。在这里，我们报道了两个功能相关基因GUCY1A3 （p.Leu163Phefs*24）和cct7 （p.Ser525Leu）的两个私有杂合突变在一个扩展的心肌梗死家族中的分离。GUCY1A3编码可溶性鸟苷环化酶（alpha 1- sgc）的α 1亚基(5)，CCT7编码无尾复合体多肽1环复合体的成员CCT eta(6)，其功能之一是稳定可溶性鸟苷环化酶。经一氧化氮刺激后，可溶性胍基环化酶产生cGMP， cGMP可诱导血管舒张，抑制血小板活化(7)。我们在体外证明，gucy1a3和CCT7突变严重降低α - 1-sGC和β - 1-sGC蛋白含量，并损害可溶性胍基环化酶活性。此外，来自基因突变携带者的血小板含有较少的可溶性guanylyl环化酶蛋白，因此显示出一氧化氮诱导的cGMP形成减少。缺乏α 1-sGC蛋白的小鼠局部创伤后微循环血栓形成加速。从一个严重受影响的家庭开始，我们已经确定了可溶性胍基环化酶依赖性一氧化氮信号受损与心肌梗死风险之间的联系，可能是通过加速血栓形成。逆转这一缺陷可能为降低心肌梗死风险提供新的治疗靶点。
Myocardial infarction, a leading cause of death intheWesternworld(1), usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery(2). The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history(3). Nextgeneration sequencing in families with several affected individuals has revolutionized mutation identification(4). Here we report the segregation of two private, heterozygous mutations in two functionally relatedgenes, GUCY1A3 (p.Leu163Phefs*24) andCCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the alpha 1 subunit of soluble guanylyl cyclase (alpha 1-sGC)(5), and CCT7 encodes CCT eta, a member of the tailless complex polypeptide 1 ring complex(6), which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation(7). Wedemonstratein vitro that mutations inbothGUCY1A3 and CCT7 severely reduce alpha 1-sGC as well as beta 1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxideinduced cGMP formation. Mice deficient in alpha 1-sGC protein displayed accelerated thrombus formation in themicrocirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.