谷胱甘肽S-转移酶P基因缺陷增加心肌对缺血再灌注损伤的敏感性。
Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury.
作者信息
Conklin Daniel J, Guo Yiru, Jagatheesan Ganapathy, Kilfoil Peter J, Haberzettl Petra, Hill Bradford G, Baba Shahid P, Guo Luping, Wetzelberger Karin, Obal Detlef, Rokosh D Gregg, Prough Russell A, Prabhu Sumanth D, Velayutham Murugesan, Zweier Jay L, Hoetker J David, Riggs Daniel W, Srivastava Sanjay, Bolli Roberto, Bhatnagar Aruni
机构信息
From the Diabetes and Obesity Center (D.J.C., G.J., P.J.K., P.H., B.G.H., S.P.B., L.G., K.W., D.O., D.G.R., J.D.H., D.W.R., S.S., R.B., A.B.), Institute of Molecular Cardiology (D.J.C., Y.G., P.J.K., P.H., B.G.H., S.P.B., D.O., D.G.R., S.S., R.B., A.B.), Division of Cardiovascular Medicine, Department of Medicine (D.J.C., Y.G., G.J., P.J.K., P.H., B.G.H., S.P.B., L.G., D.O., D.G.R., J.D.H., D.W.R., S.S., R.B., A.B), Department of Anesthesiology and Perioperative Medicine (D.O.), and Department of Biochemistry and Molecular Genetics (P.J.K., R.A.P., A.B.), University of Louisville, KY; Division of Cardiovascular Disease, University of Alabama at Birmingham (S.D.P.); and Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus (M.V., J.L.Z.).
出版信息
Circ Res. 2015 Aug 14;117(5):437-49. doi: 10.1161/CIRCRESAHA.114.305518. Epub 2015 Jul 13.
RATIONALE
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.
OBJECTIVE
We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury.
METHODS AND RESULTS
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 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 of 4-hydroxy-trans-2-nonenal or trans-2-hexanal; on ischemia, the GSTP-null hearts accumulated more acrolein-modified proteins than wild-type hearts. GSTP deficiency did not affect I/R-induced free radical generation, c-Jun N-terminal kinase 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 wild-type myocytes to acrolein-induced protein crosslinking and cell death.
CONCLUSIONS
GSTP protects the heart from I/R injury by facilitating the detoxification of cytotoxic aldehydes, such as acrolein.
理论依据
心肌缺血再灌注（I/R）会导致氧衍生自由基的产生以及脂质过氧化衍生不饱和醛的积累。然而，醛类对心肌I/R损伤的作用尚未得到评估。
目的
我们检验了谷胱甘肽S-转移酶P（GSTP）去除醛类可减轻I/R损伤这一假说。
方法与结果
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，且GSTP活性占总GST活性的很大一部分。mGstp1/2缺失降低了总GST活性，但未观察到GSTA和GSTM或主要抗氧化酶的代偿性增加。GSTP基因缺陷并未改变心脏功能，但与野生型小鼠心脏相比，GSTP基因敲除小鼠的心脏对I/R损伤更敏感。GSTP基因破坏还增加了原位冠状动脉闭塞后的梗死面积。缺血显著增加了心脏中的丙烯醛，GSTP缺乏导致不饱和醛丙烯醛代谢出现显著缺陷，但对4-羟基反式-2-壬烯醛或反式-2-己醛的代谢无影响；缺血时，GSTP基因敲除心脏比野生型心脏积累了更多丙烯醛修饰的蛋白质。GSTP缺乏不影响I/R诱导的自由基生成、c-Jun氨基末端激酶激活或还原型谷胱甘肽的消耗。丙烯醛暴露导致INa出现超极化偏移，且钠/钙交换抑制剂SN-6可延迟丙烯醛诱导的细胞死亡。从GSTP基因敲除心脏分离的心肌细胞比野生型心肌细胞对丙烯醛诱导的蛋白质交联和细胞死亡更敏感。
结论
GSTP通过促进细胞毒性醛类（如丙烯醛）的解毒作用来保护心脏免受I/R损伤。
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