Targeted inactivation of cystic fibrosis transmembrane conductance regulator chloride channel gene prevents ischemic preconditioning in isolated mouse heart
Targeted inactivation of cystic fibrosis transmembrane conductance regulator chloride channel gene prevents ischemic preconditioning in isolated mouse heart
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DOI：
10.1161/01.cir.0000138110.84758.bb
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发表时间：
2004-08-10
期刊：
影响因子：
37.8
通讯作者：
Duan, DY
中科院分区：
文献类型：
--
作者：
Chen, H;Liu, LL;Duan, DY
背景-最近的证据表明，氯离子通道可能参与缺血预处理（IPC）。在这项研究中，我们测试了囊性纤维化跨膜传导调节因子（CFTR）氯离子通道是否在心脏中表达，并由蛋白激酶A和蛋白激酶C激活，在来自野生型（WT）和CFTR敲除（CFTR-/-）小鼠的分离的心脏制备物中对于IPC是重要的。（B6.129P2-Cftr（tm 1Unc）和STOCKCftr（tm 1Unc）-TgN 1 Jaw）小鼠，并以Langendorff或工作心脏模式灌注。所有心脏稳定10分钟后进行全脑缺血30或45分钟再灌注40分钟（对照组）或全脑缺血30或45分钟再灌注40分钟（IPC组）前3个循环的5分钟缺血再灌注（IPC组）。记录血流动力学指标评价心功能。以冠脉流出液中磷酸肌酸激酶（CPK）的释放量和心肌梗死面积来评价心肌组织损伤。在WT成人心脏中，IPC在再灌注期间保护心脏功能，并显著减少缺血诱导的CPK释放和梗死面积。选择性CFTR通道阻断剂吉非罗齐可消除IPC的保护作用。此外，有针对性的失活的CFTR基因在2个不同品系的CFTR-/-小鼠也阻止IPC的保护心脏功能和心肌损伤对持续ischemia. Conclusions CFTR氯离子通道可能作为一种新的和重要的介质在小鼠心脏IPC。
Background-Recent evidence suggests that chloride channels may be involved in ischemic preconditioning (IPC). In this study, we tested whether the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels, which are expressed in the heart and activated by protein kinase A and protein kinase C, are important for IPC in isolated heart preparations from wild-type (WT) and CFTR knockout (CFTR-/-) mice.Methods and Results-Hearts were isolated from age-matched WT or CFTR-/- (B6.129P2-Cftr(tm1Unc) and STOCKCftr(tm1Unc)-TgN 1Jaw) mice and perfused in the Langendorff or working-heart mode. All hearts were allowed to stabilize for 10 minutes before they were subjected to 30 or 45 minutes of global ischemia followed by 40 minutes of reperfusion (control group) or 3 cycles of 5 minutes of ischemia and reperfusion (IPC group) before 30 or 45 minutes of global ischemia and 40 minutes of reperfusion. Hemodynamic indices were recorded to evaluate cardiac functions. Release of creatine phosphate kinase (CPK) in the samples of coronary effluent and infarct size of the ventricles were used to estimate myocardial tissue injury. In WT adult hearts, IPC protected cardiac function during reperfusion and significantly decreased ischemia-induced CPK release and infarct size. A selective CFTR channel blocker, gemfibrozil, abrogated the protective effect of IPC. Furthermore, targeted inactivation of the CFTR gene in 2 different strains of CFTR-/- mice also prevented IPC's protection of cardiac function and myocardial injury against sustained ischemia.Conclusions-CFTR Cl- channels may serve as novel and crucial mediators in mouse heart IPC.