Thirunavukkarasu Mahesh, Penumathsa Suresh Varma, Koneru Srikanth, Juhasz Bela, Zhan Lijun, Otani Hajime, Bagchi Debasis, Das Dipak K, Maulik Nilanjana
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Medical Center, 263 Farmington Avenue, Farmington, CT 06030-1110, USA.
Free Radic Biol Med. 2007 Sep 1;43(5):720-9. doi: 10.1016/j.freeradbiomed.2007.05.004. Epub 2007 May 10.
Excessive oxidative stress has been implicated in the pathology and complications of diabetes, which leads to myocardial ischemia reperfusion injury. The present study was designed to examine whether resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic compound present in red wine has a direct cardioprotective effect on diabetic myocardium. Resveratrol (2.5 mg/kg body wt/day) and L-NAME (25 mg/kg body wt/day) were administered orally for 15 days to streptozotocin (65 mg/kg)-induced diabetic rats. Sprague Dawley rats were divided into 5 groups: (i) control, (ii) diabetic, (iii) diabetic+resveratrol, (iv) diabetic+resveratrol+L-NAME (nitric oxide synthase inhibitor), and (v) diabetic+L-NAME. In our present study resveratrol demonstrated significant reduction in glucose level in diabetic rats. After the treatment, the hearts were excised and subjected to 30 min of global ischemia followed by 2 h of reperfusion. Resveratrol-treated diabetic rats demonstrated significant reduction in glucose levels as compared to the nontreated diabetic animals, and improved left ventricular function throughout reperfusion compared to the diabetic or L-NAME-treated animals (dp/dt(max) 1457+/-51 vs 999+/-44 mm Hg/s at 120 min reperfusion). Cardioprotection from ischemic injury in resveratrol-treated diabetic rats showed decreased infarct size (42% vs 51%) and cardiomyocyte apoptosis (35% vs 40%) as compared with diabetic animals. Resveratrol produced significant induction of p-AKT, p-eNOS, Trx-1, HO-1, and VEGF in addition to increased activation of MnSOD activity in diabetic animals compared to nondiabetic animals. However treatment with L-NAME in resveratrol-treated and nontreated diabetic animals demonstrated significant downregulation of the above-noted protein expression profile and MnSOD activity. In the present study we found that the mechanism(s) responsible for the cardioprotective effect of resveratrol in the diabetic myocardium include upregulation of Trx-1, NO/HO-1, and VEGF in addition to increased MnSOD activity and reduced blood glucose level. Thus this study shows a novel mechanism of pharmacological preconditioning with resveratrol in the diabetic myocardium.
过度的氧化应激与糖尿病的病理及并发症相关，而糖尿病会导致心肌缺血再灌注损伤。本研究旨在探究红酒中含有的多酚类化合物白藜芦醇（反式-3,5,4'-三羟基芪）是否对糖尿病心肌具有直接的心脏保护作用。将白藜芦醇（2.5毫克/千克体重/天）和L-硝基精氨酸甲酯（L-NAME，25毫克/千克体重/天）口服给予链脲佐菌素（65毫克/千克）诱导的糖尿病大鼠，持续15天。将斯普拉格-道利大鼠分为5组：（i）对照组，（ii）糖尿病组，（iii）糖尿病+白藜芦醇组，（iv）糖尿病+白藜芦醇+L-NAME（一氧化氮合酶抑制剂）组，以及（v）糖尿病+L-NAME组。在我们目前的研究中，白藜芦醇使糖尿病大鼠的血糖水平显著降低。治疗后，取出心脏，进行30分钟的全心缺血，随后再灌注2小时。与未治疗的糖尿病动物相比，白藜芦醇治疗的糖尿病大鼠血糖水平显著降低，并且与糖尿病或L-NAME治疗的动物相比，在整个再灌注过程中左心室功能得到改善（再灌注120分钟时dp/dt(max)为1457±51毫米汞柱/秒，而999±44毫米汞柱/秒）。与糖尿病动物相比，白藜芦醇治疗的糖尿病大鼠对缺血损伤的心脏保护作用表现为梗死面积减小（42%对51%）和心肌细胞凋亡减少（35%对40%）。与非糖尿病动物相比，白藜芦醇除了增加糖尿病动物中锰超氧化物歧化酶（MnSOD）活性的激活外，还显著诱导了p-AKT、p-eNOS、硫氧还蛋白-1（Trx-1）、血红素加氧酶-1（HO-1）和血管内皮生长因子（VEGF）。然而，在白藜芦醇治疗和未治疗的糖尿病动物中使用L-NAME治疗显示上述蛋白质表达谱和MnSOD活性显著下调。在本研究中，我们发现白藜芦醇对糖尿病心肌具有心脏保护作用的机制包括上调Trx-1、NO/HO-1和VEGF，此外还包括增加MnSOD活性和降低血糖水平。因此，本研究揭示了白藜芦醇在糖尿病心肌中进行药理预处理的一种新机制。
