Cardioprotective Effects of Luteolin on Ischemia/Reperfusion Injury in Diabetic Rats Are Modulated by eNOS and the Mitochondrial Permeability Transition Pathway
Cardioprotective Effects of Luteolin on Ischemia/Reperfusion Injury in Diabetic Rats Are Modulated by eNOS and the Mitochondrial Permeability Transition Pathway
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DOI：
10.1097/fjc.0000000000000202
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发表时间：
2015-04
影响因子：
3
通讯作者：
Jin-Ting Yang;Ling-Bo Qian;Feng-Jiang Zhang;Jue Wang;Heng Ai;Li-hui Tang;Hui‐ping Wang
中科院分区：
文献类型：
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作者：
Jin-Ting Yang;Ling-Bo Qian;Feng-Jiang Zhang;Jue Wang;Heng Ai;Li-hui Tang;Hui‐ping Wang
摘要：糖尿病心肌缺血/再灌注（I/R）损伤与氧化应激、内皮型一氧化氮合酶（eNOS）功能障碍和线粒体崩溃有关，而已知毛地黄黄酮可保护心血管系统免受糖尿病和I/R损伤。在这里，我们研究了毛地黄黄酮预处理是否通过影响eNOS和线粒体通透性转换孔（mPTP）减少糖尿病大鼠心肌I/R损伤。链脲佐菌素（65 mg/kg）治疗3周后，分别灌胃毛地黄黄酮（100 mg·kg-1·d-1）或L-NAME（25 mg·kg-1·d-1）2周。然后分离心脏，并进行30分钟的全脑缺血，随后进行120分钟的再灌注。毛地黄黄酮预处理可显著改善糖尿病I/R大鼠左室功能和冠脉流量，增加心肌组织活力和锰超氧化物歧化酶（MnSOD）活性，降低冠脉乳酸脱氢酶释放和心肌丙二醛水平。L-NAME可明显减弱木犀草素的上述改善作用。Luteolin还显着上调I/R后糖尿病大鼠心脏eNOS的表达。Ca 2+诱导的mPTP开放和线粒体内膜电位降低显着抑制分离自木犀草素处理的糖尿病大鼠心室肌细胞，这种影响被减弱L-NAME。这些结果表明，毛地黄黄酮保护糖尿病心脏免受I/R损伤通过上调心肌eNOS途径，下游效应包括MnSOD的增强和mPTP的抑制。
Abstract: Myocardial ischemia/reperfusion (I/R) injury in diabetes is associated with oxidative stress, endothelial nitric oxide synthase (eNOS) dysfunction, and mitochondrial collapse, whereas luteolin is known to protect the cardiovascular system against diabetes and I/R injury. Here, we investigated whether luteolin pretreatment diminishes myocardial I/R injury in diabetic rats by affecting eNOS and the mitochondrial permeability transition pore (mPTP). After diabetic rats were produced by streptozotocin treatment (65 mg/kg) for 3 weeks, luteolin (100 mg·kg−1·d−1) or L-NAME (25 mg·kg−1·d−1) was administered intragastrically for 2 weeks. Hearts were then isolated and subjected to 30 minutes of global ischemia followed by 120 minutes of reperfusion. Pretreatment with luteolin significantly improved left ventricular function and coronary flow throughout reperfusion, increased cardiac tissue viability and manganese superoxide dismutase (MnSOD) activity, and reduced coronary lactate dehydrogenase release, and the myocardial malonaldehyde level in diabetic I/R rat hearts. All these improving effects of luteolin were significantly attenuated by L-NAME. Luteolin also significantly upregulated eNOS expression in diabetic rat hearts after I/R. Ca2+-induced mPTP opening and mitochondrial inner membrane potential reduction were significantly inhibited in ventricular myocytes isolated from luteolin-treated diabetic rats, and this effect was attenuated by L-NAME. These findings indicate that luteolin protects the diabetic heart against I/R injury by upregulating the myocardial eNOS pathway, and downstream effects include the enhancement of MnSOD and inhibition of mPTP.