Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury.
Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury.
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DOI：
10.1161/circresaha.114.305518
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发表时间：
2015-08-14
影响因子：
20.1
通讯作者：
Bhatnagar A
中科院分区：
文献类型：
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作者：
Conklin DJ;Guo Y;Jagatheesan G;Kilfoil PJ;Haberzettl P;Hill BG;Baba SP;Guo L;Wetzelberger K;Obal D;Rokosh DG;Prough RA;Prabhu SD;Velayutham M;Zweier JL;Hoetker JD;Riggs DW;Srivastava S;Bolli R;Bhatnagar A
心肌缺血再灌注（I/R）导致氧源性自由基的产生和脂质过氧化衍生的不饱和醛的积累。然而，醛类物质对心肌I/R损伤的影响尚未得到评估。我们验证了假设，即通过谷胱甘肽s -转移酶P （GSTP）去除醛可以减少I/R损伤。在成年雄性C57BL/6小鼠心脏中，Gstp1/2是最丰富的GST转录本，其次是Gsta4和Gstm4.1， GSTP活性占GST总活性的很大一部分。mGstp1/2缺失降低了GST总活性，但GSTA和GSTM或主要抗氧化酶没有代偿性增加。GSTP基因缺失不会改变心功能，但与野生型（WT）小鼠的心脏相比，GSTP缺失小鼠的心脏对I/R损伤更敏感。GSTP基因的破坏也增加了冠状动脉原位闭塞后的梗死面积。缺血显著增加心脏内丙烯醛，GSTP缺乏导致不饱和醛、丙烯醛代谢显著不足，但对4-羟基反式-2-壬烯醛（HNE）和反式-2-己醛代谢无明显影响；缺血后，gstp缺失的心脏比WT心脏积累了更多的丙烯醛修饰蛋白。gstp缺乏不影响I/ r诱导的自由基生成、JNK激活或还原性谷胱甘肽的消耗。丙烯醛暴露诱导了INa的超极化移位，并且丙烯醛诱导的细胞死亡被SN-6（一种Na+/Ca++交换抑制剂）延迟。从gstp缺失的心脏分离的心肌细胞比WT心肌细胞对丙烯醛诱导的蛋白交联和细胞死亡更敏感。GSTP通过促进细胞毒性醛（如丙烯醛）的解毒，保护心脏免受I/R损伤。
Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed. We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury. In adult male C57BL/6 mouse hearts, Gstp1/2 was the most abundant GST transcript followed by Gsta4 and Gstm4.1, and GSTP activity was a significant fraction of the total GST activity. mGstp1/2 deletion reduced total GST activity, but no compensatory increase in GSTA and GSTM or major antioxidant enzymes was observed. Genetic deficiency of GSTP did not alter cardiac function, but in comparison with hearts from wild-type (WT) mice, the hearts isolated from GSTP-null mice were more sensitive to I/R injury. Disruption of the GSTP gene also increased infarct size after coronary occlusion in situ. Ischemia significantly increased acrolein in hearts, and GSTP deficiency induced significant deficits in the metabolism of the unsaturated aldehyde, acrolein, but not in the metabolism 4-hydroxy-trans-2-nonenal (HNE) or trans-2-hexanal; and, upon ischemia, the GSTP-null hearts accumulated more acrolein-modified proteins than WT hearts. GSTP-deficiency did not affect I/R-induced free radical generation, JNK activation or depletion of reduced glutathione. Acrolein-exposure induced a hyperpolarizing shift in INa, and acrolein-induced cell death was delayed by SN-6, a Na+/Ca++ exchange inhibitor. Cardiomyocytes isolated from GSTP-null hearts were more sensitive than WT myocytes to acrolein-induced protein crosslinking and cell death. GSTP protects the heart from I/R injury by facilitating the detoxification of cytotoxic aldehydes such as acrolein.