Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase.
Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase.
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DOI：
10.1016/s0895-7061(98)00235-0
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发表时间：
1999-02
影响因子：
3.2
通讯作者：
Ding Wang;Xiao-Ping Yang;Yun-he Liu;Oscar A. Carretero;M. Lapointe
中科院分区：
文献类型：
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作者：
Ding Wang;Xiao-Ping Yang;Yun-he Liu;Oscar A. Carretero;M. Lapointe
诱导型一氧化氮合酶异构体(INOS)在包括心肌细胞在内的多种细胞中被细胞因子和内毒素上调。细胞因子诱导的一氧化氮(NO)具有细胞毒性，与心肌梗死、心肌病和感染性休克的病理生理学密切相关。为了探讨诱导型一氧化氮合酶(INOS)在缺血心肌中的作用，我们研究了：1)雄性SD大鼠心肌梗死后iNOS mRNA表达的时程及梗死区iNOS蛋白的表达；2)体外缺氧是否是诱导型一氧化氮合酶表达的潜在中介；3)两种不同的选择性抑制剂(氨基胍和甲基异硫脲硫酸盐)对体内iNOS的抑制是否影响梗塞面积。通过结扎冠状动脉左前降支(LAD)建立心肌梗死模型，并于结扎和假手术后的不同时间采集心肌组织。在左心室梗死区诱导iNOS mRNA表达7d，同时在梗死区检测到iNOS蛋白的表达。接下来，我们测试了低氧是否会在体外诱导iNOS。在培养的新生大鼠心肌细胞中，低氧6~24 h可轻微诱导iNOS mRNA表达，但只有在细胞因子IL-1β存在的情况下才能检测到iNOS蛋白的表达。为了研究诱导型一氧化氮合酶(INOS)活性是否与心肌损伤(如梗塞面积)有关，我们在左前降支阻断前24小时给予第一剂一氧化氮合酶抑制剂，然后在手术后给予第二剂。用氨基胍抑制iNOS活性可使心肌梗死面积减少20%，但对中性粒细胞的浸润无影响，而选择性更强的抑制剂甲基异硫脲则可使心肌梗死面积减少41%。这些数据表明，iNOS亚型衍生的NO可能通过导致心脏缺血区附近区域的心肌细胞死亡而导致心肌梗死后的部分心肌损伤。Am J Hyperten 1999；12：174-182©1999美国高血压杂志。
The inducible nitric oxide synthase isoform (iNOS) is upregulated by cytokines and endotoxins in many types of cells, including cardiac myocytes. Nitric oxide (NO) induced by cytokines can be cytotoxic, and has been implicated in the pathophysiology of myocardial infarction, cardiomyopathy, and septic shock. To examine the role of iNOS in the ischemic myocardium, we studied: 1) the time course of expression of iNOS mRNA after myocardial infarction (MI) in male Sprague-Dawley rat hearts and expression of iNOS protein in the infarcted region; 2) whether hypoxia in vitro is a potential mediator of the induction of iNOS mRNA; and 3) whether inhibition of iNOS by two different selective inhibitors (aminoguanidine andS-methylisothiourea sulfate) in vivo influences infarct size. Myocardial infarction was induced by ligation of the left anterior descending coronary artery (LAD), and tissue was collected at selected times thereafter from both ligated and sham-operated rats. iNOS mRNA was induced in the infarcted region of the left ventricle for 7 days; iNOS protein was also detected in the infarcted area. We next tested whether hypoxia would induce iNOS in vitro. In cultured neonatal ventricular myocytes, iNOS mRNA was slightly induced by 6 to 24 h of hypoxia; however, iNOS protein was only detected when the cytokine interleukin-1β was present. To study whether iNOS activity contributed to myocardial damage (eg, infarct size), we administered the first dose of the NOS inhibitors 24 h before LAD occlusion and then a second dose after surgery. Inhibition of iNOS activity with aminoguanidine reduced infarct size by 20% but had no effect on infiltration by neutrophils, whereas the more selective inhibitorS-methylisothiourea sulfate reduced infarct size by 41%. These data suggest that NO derived from the iNOS isoform contributes to some of the myocardial injury following MI, possibly by causing myocardial cell death in areas bordering the ischemic region of the heart. Am J Hypertens 1999;12:174–182 © 1999 American Journal of Hypertension, Ltd.