Exogenous NADPH ameliorates myocardial ischemia-reperfusion injury in rats through activating AMPK/mTOR pathway.
Exogenous NADPH ameliorates myocardial ischemia-reperfusion injury in rats through activating AMPK/mTOR pathway.
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外源性NADPH通过激活AMPK/mTOR通路改善大鼠心肌缺血再灌注损伤。
DOI：
10.1038/s41401-019-0301-1
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发表时间：
2020
影响因子：
8.2
通讯作者：
Xie Hong
中科院分区：
文献类型：
--
作者：
Zhu Jiang;Wang Yi-Fei;Chai Xiao-Ming;Qian Ke;Zhang Ling-Wei;Peng Peng;Chen Pei-Min;Cao Jian-Fang;Qin Zheng-Hong;Sheng Rui;Xie Hong
我们前期的研究表明，烟酰胺腺嘌呤二核苷酸磷酸（nicotinamide adenine dinucleotide phosphate， NADPH）对脑缺血损伤具有重要的保护作用。在这项研究中，我们研究了NADPH是否对心肌缺血/再灌注（I/R）损伤具有心脏保护作用。结扎冠状动脉左前降支30min，再灌注2h，诱导心肌I/R损伤。在再灌注开始时给药NADPH（4、8、16 mg·kg−1·d−1,iv）。我们发现，在静脉给药后4小时，血浆和心脏中的NADPH浓度显著升高。外源性NADPH （8 ~ 16 mg/kg）显著降低心肌梗死面积，降低血清乳酸脱氢酶（LDH）和心肌肌钙蛋白I （cTn-I）水平。外源性NADPH显著降低心肌细胞凋亡率，减少PARP和caspase-3的裂解。此外，外源性NADPH降低线粒体空泡化，增加线粒体膜蛋白COXIV和TOM20，降低BNIP3L，增加Bcl-2，以保护线粒体功能。我们对新生大鼠心肌细胞（NRCM）进行了氧葡萄糖剥夺/恢复（OGD/R）的体外实验。NADPH预处理（60、500 nM）可显著提高细胞活力，抑制OGD/ r诱导的细胞凋亡。在OGD/ r处理的NRCM中，NADPH预处理显著增加了AMPK的磷酸化，下调了mTOR的磷酸化。化合物C是一种AMPK抑制剂，在OGD/ r处理的NRCM中，可以消除nadph诱导的AMPK磷酸化和心脏保护作用。综上所述，外源性NADPH通过激活AMPK/mTOR通路，抑制线粒体损伤和心肌细胞凋亡，对心肌I/R损伤具有保护作用。NADPH可能是预防和治疗心肌缺血性疾病的潜在候选物。
Our previous study shows that nicotinamide adenine dinucleotide phosphate (NADPH) plays an important role in protecting against cerebral ischemia injury. In this study we investigated whether NADPH exerted cardioprotection against myocardial ischemia/reperfusion (I/R) injury. To induce myocardial I/R injury, rats were subjected to ligation of the left anterior descending branch of coronary artery for 30 min followed by reperfusion for 2 h. At the onset of reperfusion, NADPH (4, 8, 16 mg· kg−1· d−1, iv) was administered to the rats. We found that NADPH concentrations in plasma and heart were significantly increased at 4 h after intravenous administration. Exogenous NADPH (8−16 mg/kg) significantly decreased myocardial infarct size and reduced serum levels of lactate dehydrogenase (LDH) and cardiac troponin I (cTn-I). Exogenous NADPH significantly decreased the apoptotic rate of cardiomyocytes, and reduced the cleavage of PARP and caspase-3. In addition, exogenous NADPH reduced mitochondrial vacuolation and increased mitochondrial membrane protein COXIV and TOM20, decreased BNIP3L and increased Bcl-2 to protect mitochondrial function. We conducted in vitro experiments in neonatal rat cardiomyocytes (NRCM) subjected to oxygen–glucose deprivation/restoration (OGD/R). Pretreatment with NADPH (60, 500 nM) significantly rescued the cell viability and inhibited OGD/R-induced apoptosis. Pretreatment with NADPH significantly increased the phosphorylation of AMPK and downregulated the phosphorylation of mTOR in OGD/R-treated NRCM. Compound C, an AMPK inhibitor, abolished NADPH-induced AMPK phosphorylation and cardioprotection in OGD/R-treated NRCM. In conclusion, exogenous NADPH exerts cardioprotection against myocardial I/R injury through the activation of AMPK/mTOR pathway and inhibiting mitochondrial damage and cardiomyocyte apoptosis. NADPH may be a potential candidate for the prevention and treatment of myocardial ischemic diseases.