The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury
The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury
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DOI：
10.1152/ajpheart.00906.2012
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发表时间：
2013-04-01
影响因子：
4.8
通讯作者：
Cheung, Joseph Y.
中科院分区：
文献类型：
--
作者：
Miller, Barbara A.;Wang, JuFang;Cheung, Joseph Y.
米勒·巴、王J、赫希勒-拉兹凯维奇一世、高娥、宋军、张旭、科赫·WJ、麦德什·M、马利兰卡拉曼·K、顾田、陈S、K·科弗、康拉德·K、费尔德曼·AM、张俊贤。瞬时受体家族的第二个成员--美司他丁通道对心脏的缺血再灌注损伤具有保护作用。Am J Physiol心圈Physiol 304：H1010-H1022,2013。2013年2月1日首次出版；doi：10.1152/ajpheart.00906.2012。-瞬时受体潜力-Melastatin通道家族的第二个成员(TRPM2)在心脏和血管系统中表达。TRPM2通道表达于成人左心室肌细胞的肌膜和横管。在野生型(WT)心肌细胞中，TRPM2通道明显高于TRPM2基因敲除(KO)型心肌细胞，而克霉唑可抑制野生型(WT)心肌细胞的钙内流。安静时，WT和KO心脏的LV质量、心率、短轴缩短率和+dp/dt无差异。在缺血再灌注(I/R)后2-3天，尽管危险区域和梗塞面积相似，但KO心脏的短轴缩短率和+dp/dt均低于WT心脏。与WT I/R细胞相比，KO I/R细胞Na+/Ca~(2+)交换器(NCX1)和NCX1电流表达增加，Na+-K+-ATPaseα(1)亚基表达和Na+泵电流减少，动作电位时程延长。WT和KO心肌细胞I/R后，细胞内钙离子浓度瞬变和收缩幅度均受到抑制。低氧2 h复氧30min后，KO细胞内ROS水平明显高于WT LV细胞。与WT I/R心脏相比，KO I/R心脏的氧自由基清除酶(SODS)及其上游调节因子(叉头盒转录因子和低氧诱导因子)较低，而NADPH氧化酶较高。我们得出结论，TRPM2通道通过减少ROS的产生和增强对ROS的清除，从而减轻I/R诱导的氧化应激，从而保护心脏免受I/R损伤。
Miller BA, Wang J, Hirschler-Laszkiewicz I, Gao E, Song J, Zhang X, Koch WJ, Madesh M, Mallilankaraman K, Gu T, Chen S, Keefer K, Conrad K, Feldman AM, Cheung JY. The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 304: H1010-H1022, 2013. First published February 1, 2013; doi:10.1152/ajpheart.00906.2012.-The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 channels were functional since activation with H2O2 resulted in Ca2+ influx that was dependent on extracellular Ca2+, was significantly higher in wild-type (WT) myocytes compared with TRPM2 knockout (KO) myocytes, and inhibited by clotrimazole in WT myocytes. At rest, there were no differences in LV mass, heart rate, fractional shortening, and +dP/dt between WT and KO hearts. At 2-3 days after ischemia-reperfusion (I/R), despite similar areas at risk and infarct sizes, KO hearts had lower fractional shortening and +dP/dt compared with WT hearts. Compared with WT I/R myocytes, expression of the Na+/Ca2+ exchanger (NCX1) and NCX1 current were increased, expression of the alpha(1)-subunit of Na+-K+-ATPase and Na+ pump current were decreased, and action potential duration was prolonged in KO I/R myocytes. Post-I/R, intracellular Ca2+ concentration transients and contraction amplitudes were equally depressed in WT and KO myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation, levels of ROS were significantly higher in KO compared with WT LV myocytes. Compared with WT I/R hearts, oxygen radical scavenging enzymes (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factor) were lower, whereas NADPH oxidase was higher, in KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/R-induced oxidative stress.