Protective Role of Cardiac CFTR Activation Upon Early Reperfusion Against Myocardial Infarction
Protective Role of Cardiac CFTR Activation Upon Early Reperfusion Against Myocardial Infarction
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DOI：
10.1159/000341479
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发表时间：
2012-09
影响因子：
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通讯作者：
H. Uramoto;Toshiaki Okada;Yasunobu Okada
中科院分区：
文献类型：
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作者：
H. Uramoto;Toshiaki Okada;Yasunobu Okada
背景资料：囊性纤维化跨膜传导调节因子（CFTR）的心脏亚型被β-肾上腺素能或嘌呤能刺激激活，并参与渗透性肿胀后的细胞体积调节。此外，心脏CFTR据报道是必不可少的机制，缺血预处理保护缺血/再灌注（I/ R）诱导的心脏损伤。在这里，我们探讨了激活心脏CFTR可以提供保护，防止I/R诱导的心肌梗死，即使在缺血发作的可能性。研究方法：将野生型小鼠的心脏进行30或40分钟的左冠状动脉闭塞，然后在体内再灌注2小时或2天，并在各种条件下检查心肌梗死。原代培养的新生大鼠心室肌细胞在体外进行缺氧/复氧，并检查坏死细胞死亡。结果：CFTR基因敲除小鼠的梗死面积比野生型小鼠大得多。静脉输注一些假定的CFTR激活剂在再灌注后显着减少野生型但不是CFTR缺陷小鼠心肌梗死的大小。这种保护作用通过共同施用CFTR抑制剂而消除。CFTR激活剂以对CFTR抑制剂敏感的方式改善了体内I/R小鼠血清中心肌特异性肌酸激酶同工酶的释放。CFTR激活剂或CFTR基因过表达可减轻体外培养的新生大鼠心室肌细胞缺氧/复氧后的坏死性死亡，但CFTR抑制剂或CFTR基因沉默可加重其坏死性死亡。结论：结论：再灌注早期内源性心肌CFTR的激活参与了体内和体外I/R引起的心肌坏死损伤的保护作用。心脏CFTR可以作为一个目标，即使在缺血发作后，药物干预I/R诱导的心肌梗死。
Background: The cardiac isoform of the cystic fibrosis transmembrane conductance regulator (CFTR) was shown to be activated by β-adrenergic or purinergic stimulation and involved in cell volume regulation after osmotic swelling. Also, cardiac CFTR was reported to be essential in the mechanism by which ischemic preconditioning protects against ischemia/reperfusion(I/ R)-induced injury of the heart. Here, we explored the possibility that activation of cardiac CFTR can provide protection against I/R-induced myocardial infarction, even after ischemic attack. Methods: The hearts of wild-type mice were subjected to 30- or 40-min left coronary artery occlusion followed by 2-h or 2-day reperfusion in vivo, and myocardial infarction was examined under a variety of conditions. Neonetal rat ventricular myocytes in primary culture were subjected to hypoxia/reoxygenation in vitro, and necrotic cell death was examined. Results: The infarct size was much greater in CFTR knockout mice than in wild-type mice. Intravenous infusion of a number of putative CFTR activators upon reperfusion prominently reduced the size of myocardial infarction in wild-type but not CFTR-deficient mice. This protective effect was abolished by co-administration of a CFTR inhibitor. CFTR activators ameliorated, in a manner sensitive to a CFTR inhibitor, release of myocardial-specific creatine kinase isoenzyme to the serum in mice subjected to I/R in vivo. Necrotic death of cultured neonatal rat ventricular myocytes subjected to hypoxia/reoxygenation in vitro was ameliorated by CFTR activators or CFTR gene overexpression but aggravated by a CFTR inhibitor or CFTR gene silencing. Conclusion: It is concluded that activation of endogenous myocardial CFTR upon early reperfusion is involved in protection against necrotic myocardial injury induced by I/R in vivo and in vitro. Cardiac CFTR may serve as a target accessible even after ischemic attack for pharmacotherapeutic intervention in I/R-induced myocardial infarction.