Telmisartan, a dual ARB/partial PPAR-γ agonist, protects myocardium from ischaemic reperfusion injury in experimental diabetes
Telmisartan, a dual ARB/partial PPAR-γ agonist, protects myocardium from ischaemic reperfusion injury in experimental diabetes
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DOI：
10.1111/j.1463-1326.2011.01377.x
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发表时间：
2011-06-01
影响因子：
5.8
通讯作者：
Arya, D. S.
中科院分区：
文献类型：
--
作者：
Goyal, S. N.;Bharti, S.;Arya, D. S.
研究方法：糖尿病大鼠随机接受溶媒（假手术和I/R）、替米沙坦（10 mg/kg/天，口服）、PPAR-γ拮抗剂GW 9662（1 mg/kg/天，腹膜内）或两者共14天。第15天，除假手术组外，结扎冠状动脉左前降支45 min，再灌注1 h。血流动力学、生化、组织病理学、超微结构、免疫组织化学结果：（1）Bax、Bcl-2蛋白表达、TUNEL阳性率、梗死面积及蛋白质印迹法（westernblot）检测结果：替米沙坦治疗通过使平均动脉压、左心室压正常化显著改善心功能（+/- LVdP/dt（max），心肌收缩和舒张的标志物），通过降低左心室舒张末期压（前负荷的标记，3.7 ± 0.41对7.3 ± 0.89，p < 0.001）和梗塞面积百分比（37.52 ± 5.83对46.27 ± 3.20，p < 0.01）。有趣的是，GW 9662抑制了I/R损伤，（梗死面积百分比，54.38 +/- 6.48 vs. 46.27 +/- 3.20，p < 0.01），而替米沙坦与GW 9662（梗塞面积百分比，41.16 +/-8.23对46.27 +/-3.20，p < 0.05）与单独的替米沙坦相比显示出较不显著的结果。此外，替米沙坦可显著改善内源性抗氧化剂、肌酸激酶-MB同工酶、乳酸脱氢酶的活性，并防止心肌中肿瘤坏死因子-α和丙二醛的增加。此外，替米沙坦还降低Bax表达，（4.45 +/- 1.24% vs. 10.25 +/-0.96%，p < 0.01），TUNEL阳性细胞数（6.2 +/- 0.98% vs. 13.0 +/- 1.6，p < 0.01）、炎症、肌坏死和Bcl-2表达增加（5.45 +/- 0.15% vs. 1.24 +/-0.3%，p < 0.01）。另一方面，单独GW 9662处理增加Bax表达和TUNEL阳性，降低Bcl-2表达。与GW 9662联合给药可部分减弱替米沙坦的保护作用。Western blot分析表明，替米沙坦治疗增强PPAR-gamma的表达，而GW 9662降低它在myocardial.Conclusions：除了类效应的ARBs，替米沙坦有一个有益的影响，在I/R损伤在糖尿病大鼠的一部分，因为激活的PPAR-gamma。
Methods: Diabetic rats were randomized to receive vehicle (sham and I/R), telmisartan (10 mg/kg/day, orally), PPAR-gamma antagonist GW9662 (1 mg/kg/day, intraperitoneally) or both for 14 days. On 15th day, excluding sham group, left anterior descending coronary artery occlusion was performed for 45 min followed by 1 h of reperfusion. Haemodynamic, biochemical, histopathological, ultrastructural, immunohistochemical (Bax and Bcl-2 protein), TUNEL positivity, infarct size and western blot studies were performed.Results: Telmisartan treatment significantly improved cardiac function by normalizing mean arterial pressure, left ventricular pressure (+/- LVdP/dt(max), a marker of myocardial contraction and relaxation), by decreasing left ventricular end-diastolic pressure (a marker of preload, 3.7 +/- 0.41 vs. 7.3 +/- 0.89, p < 0.001) and percent infarct area (37.52 +/- 5.83 vs. 46.27 +/- 3.20, p < 0.01) as compared to diabetic I/R group. Interestingly, GW9662 worsens the I/R injury (percent infarct area, 54.38 +/- 6.48 vs. 46.27 +/- 3.20, p < 0.01), whereas telmisartan with GW9662 (percent infarct area, 41.16 +/- 8.23 vs. 46.27 +/- 3.20, p < 0.05) showed lesser significant results as compared to telmisartan alone. Additionally, telmisartan significantly ameliorates activities of endogenous antioxidants, creatine kinase-MB isoenzyme, lactate dehydrogenase and prevented the increase of tumour necrosis factor-alpha and malondialdehyde in myocardium. Furthermore, telmisartan also decreased Bax expression (4.45 +/- 1.24% vs. 10.25 +/- 0.96%, p < 0.01), number of TUNEL-positive cells (6.2 +/- 0.98% vs. 13.0 +/- 1.6, p < 0.01), inflammation, myonecrosis and increased Bcl-2 expression (5.45 +/- 0.15% vs. 1.24 +/- 0.3%, p < 0.01). On the other hand, GW9662 treatment alone increased the Bax expression, TUNEL positivity and decreased Bcl-2 expression. Telmisartan protective effects were partially attenuated by a co-administration with GW9662. Western blot analysis showed that telmisartan treatment enhanced PPAR-gamma expression, whereas GW9662 decreased it in myocardium.Conclusions: In addition to the class effect of ARBs, telmisartan has a beneficial effect in I/R injury in diabetic rats in part because of activation of PPAR-gamma.