Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats.
Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats.
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DOI：
10.1371/journal.pone.0111212
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Goyal SN
中科院分区：
文献类型：
--
作者：
Agrawal YO;Sharma PK;Shrivastava B;Ojha S;Upadhya HM;Arya DS;Goyal SN
本研究观察了天然黄酮类化合物橙皮苷对糖尿病大鼠心肌缺血再灌注损伤的影响。将患有糖尿病的雄性Wistar大鼠分为5组，每天一次经口给予生理盐水（IR-假手术组和IR-对照组）、橙皮苷（100 mg/kg/天; IR-橙皮苷）、GW 9962（PPAR-γ受体拮抗剂）或两者的组合，持续14天。在第15天，在IR对照组和IR治疗组中，大鼠经受左前降支（LAD）冠状动脉闭塞45分钟，随后再灌注1小时。记录血流动力学参数，处死大鼠;分离心脏进行生化、组织病理学、超微结构和免疫组织化学。在IR对照组中，观察到显著的心室功能障碍沿着促凋亡蛋白Bax的表达增强。观察到心脏损伤标志物乳酸脱氢酶活性、CK-MB下降，硫代巴比妥酸反应物质（脂质过氧化标志物）和TNF-α含量增加。橙皮苷预处理显著改善平均动脉压，降低左心室舒张末期压，并改善心脏的正性和负性收缩功能（+LVdP/dt和-LVdP/dt）。此外，橙皮苷处理显着降低硫代巴比妥酸反应物质的水平，并逆转乳酸脱氢酶的活性向正常值。橙皮苷通过上调Bcl-2蛋白表达和降低Bax蛋白表达而发挥抗凋亡作用。此外，组织病理学和超微结构研究再次证实了橙皮苷的保护作用。而选择性PPAR-γ受体拮抗剂GW 9662则产生相反的作用，并减弱橙皮苷的改善作用。本研究首次证实橙皮苷对大鼠心肌缺血再灌注损伤的保护作用可能与过氧化物酶体增殖物激活受体-γ（PPAR-γ）通路有关。
The present study investigated the effect of hesperidin, a natural flavonoid, in cardiac ischemia and reperfusion (I/R) injury in diabetic rats. Male Wistar rats with diabetes were divided into five groups and were orally administered saline once daily (IR-sham and IR-control), Hesperidin (100 mg/kg/day; IR-Hesperidin), GW9962 (PPAR-γ receptor antagonist), or combination of both for 14 days. On the 15th day, in the IR-control and IR-treatment groups, rats were subjected to left anterior descending (LAD) coronary artery occlusion for 45 minutes followed by a one-hour reperfusion. Haemodynamic parameters were recorded and rats were sacrificed; hearts were isolated for biochemical, histopathological, ultrastructural and immunohistochemistry. In the IR-control group, significant ventricular dysfunctions were observed along with enhanced expression of pro-apoptotic protein Bax. A decline in cardiac injury markers lactate dehydrogenase activity, CK-MB and increased content of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and TNF-α were observed. Hesperidin pretreatment significantly improved mean arterial pressure, reduced left ventricular end-diastolic pressure, and improved both inotropic and lusitropic function of the heart (+LVdP/dt and –LVdP/dt) as compared to IR-control. Furthermore, hesperidin treatment significantly decreased the level of thiobarbituric acid reactive substances and reversed the activity of lactate dehydrogenase towards normal value. Hesperidin showed anti-apoptotic effects by upregulating Bcl-2 protein and decreasing Bax protein expression. Additionally, histopathological and ultrastructural studies reconfirmed the protective action of hesperidin. On the other hand, GW9662, selective PPAR-γ receptor antagonist, produced opposite effects and attenuated the hesperidin induced improvements. The study for the first time evidence the involvement of PPAR-γ pathway in the cardioprotective activity of hesperidin in I/R model in rats.
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