Characterization of a critical role for CFTR chloride channels in cardioprotection against ischemia/reperfusion injury.
Characterization of a critical role for CFTR chloride channels in cardioprotection against ischemia/reperfusion injury.
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DOI：
10.1038/aps.2011.61
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发表时间：
2011-06
影响因子：
8.2
通讯作者：
Duan, Dayue Darrel
中科院分区：
文献类型：
--
作者：
Xiang, Sunny Yang;Ye, Linda L.;Duan, Li-lu Marie;Liu, Li-hui;Ge, Zhi-dong;Auchampach, John A.;Gross, Garrett J.;Duan, Dayue Darrel
关键词：
囊性纤维化跨膜传导调节因子（CFTR）属于atp结合盒转运蛋白超家族，编码心脏中PKC和pka激活的氯离子（Cl -）通道。先前对离体小鼠心脏的研究支持CFTR在急性缺血预处理（IPC）中的潜在作用。本研究旨在进一步探讨CFTR在IPC和POC介导的早期和晚期（第二窗口）心肌缺血/再灌注（I/R）损伤保护中的功能作用。在体内I/R模型中，早期IPC显著降低了野生型（CFTR+/+）小鼠（从40.4±5.3%降至10.4±2.0%,n=8, p<0.001）和杂合型（CFTR+/ -）小鼠（从39.4±2.4%降至15.4±5.1%,n=6, p<0.001）的心肌梗死面积，但未能保护CFTR敲除（CFTR - / -）小鼠（46.9±6.2% vs 55.5±7.8%,n=6, p< 0.05）。在IPC晚期体内实验中也观察到类似的结果。此外，体内和体外POC均能显著减少CFTR+/+小鼠的心肌梗死，而在CFTR - / -小鼠中则没有。靶向灭活CFTR可消除IPC对I/R诱导的细胞凋亡的保护作用，提示激活CFTR通道抑制细胞凋亡可能是IPC和poc介导的I/R损伤心脏保护的新机制。这些结果为CFTR Cl -通道在IPC和poc介导的心肌损伤保护中发挥关键作用提供了令人信服的证据。因此，CFTR Cl -通道可能是缺血性心脏病治疗的新靶点。
The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP-binding cassette transporter superfamily and encodes a PKC- and PKA-activated chloride (Cl−) channel in the heart. Previous study in isolated mouse heart supports a potential role of CFTR in acute ischemic preconditioning (IPC). This study was designed to further investigate the functional role of CFTR in the early and late (second window) IPC- and postconditioning (POC)-mediated cardioprotection against ischemia/reperfusion (I/R) injury. In the in vivo I/R models, early IPC significantly reduced the myocardial infarct size in the wild-type (CFTR+/+) (from 40.4±5.3% to 10.4±2.0%, n=8, p<0.001) and the heterozygous (CFTR+/−) littermates (from 39.4±2.4% to 15.4±5.1%, n=6, p<0.001) but failed to protect the CFTR knockout (CFTR−/−) mice (46.9±6.2% vs 55.5±7.8%, n=6, p>0.5). Similar results were observed in the in vivo late IPC experiments. Furthermore, both in vivo and ex vivo POC significantly reduced myocardial infarction in the CFTR+/+ mice but not in the CFTR−/− mice. Targeted inactivation of CFTR abolished the protective effects of IPC on I/R-induced apoptosis, suggesting that inhibition of apoptosis by activation of CFTR channels may be a novel mechanism of IPC- and POC-mediated cardioprotection against I/R injury. These results provide compelling evidence for a critical role of CFTR Cl− channels in the IPC- and POC-mediated cardioprotection against myocardial injury. Therefore, CFTR Cl− channels may represent novel therapeutic targets for the treatment of ischemic cardiac diseases.
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DOI：
10.1016/s0022-2828(02)00277-8
发表时间：
2003-01-01
影响因子：
5
作者：
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通讯作者：
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影响因子：
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影响因子：
37.8
作者：
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影响因子：
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作者：
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