Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
PLoS One. 2013 Dec 6;8(12):e82577. doi: 10.1371/journal.pone.0082577. eCollection 2013.
Naringin has antioxidant properties that could improve redox-sensitive myocardial ischemia reperfusion (IR) injury. This study was designed to investigate whether naringin restores the myocardial damage and dysfunction in vivo after IR and the mechanisms underlying its cardioprotective effects. Naringin (20-80 mg/kg/day, p.o.) or saline were administered to rats for 14 days and the myocardial IR injury was induced on 15(th) day by occluding the left anterior descending coronary artery for 45 min and subsequent reperfusion for 60 min. Post-IR rats exhibited pronounced cardiac dysfunction as evidenced by significantly decreased mean arterial pressure, heart rate, +LVdP/dt max (inotropic state), -LVdP/dt max (lusitropic state) and increased left ventricular end diastolic pressure as compared to sham group, which was improved by naringin. Further, on histopathological and ultrastructural assessments myocardium and myocytes appeared more normal in structure and the infarct size was reduced significantly in naringin 40 and 80 mg/kg/day group. This amelioration of post-IR-associated cardiac injury by naringin was accompanied by increased nitric oxide (NO) bioavailability, decreased NO inactivation to nitrotyrosine, amplified protein expressions of Hsp27, Hsp70, β-catenin and increased p-eNOS/eNOS, p-Akt/Akt, and p-ERK/ERK ratio. In addition, IR-induced TNF-α/IKK-β/NF-κB upregulation and JNK phosphorylation were significantly attenuated by naringin. Moreover, western blotting and immunohistochemistry analysis of apoptotic signaling pathway further established naringin cardioprotective potential as it upregulated Bcl-2 expression and downregulated Bax and Caspase-3 expression with reduced TUNEL positivity. Naringin also normalized the cardiac injury markers (lactate dehydrogenase and creatine kinase-MB), endogenous antioxidant activities (superoxide dismutase, reduced glutathione and glutathione peroxidase) and lipid peroxidation levels. Thus, naringin restored IR injury by preserving myocardial structural integrity and regulating Hsp27, Hsp70, p-eNOS/p-Akt/p-ERK signaling and inflammatory response.
柚皮苷具有抗氧化特性，可改善氧化还原敏感的心肌缺血再灌注（IR）损伤。本研究旨在探讨柚皮苷是否能恢复 IR 后体内的心肌损伤和功能障碍，以及其心脏保护作用的机制。柚皮苷（20-80mg/kg/天，口服）或生理盐水连续给药 14 天，第 15 天通过阻断左前降支冠状动脉 45 分钟，随后再灌注 60 分钟诱导心肌 IR 损伤。与假手术组相比，IR 后大鼠表现出明显的心功能障碍，表现为平均动脉压、心率、+LVdP/dt max（收缩状态）、-LVdP/dt max（舒张状态）显著降低，左心室舒张末期压升高，而柚皮苷可改善这些变化。此外，在组织病理学和超微结构评估中，心肌和心肌细胞的结构更为正常，柚皮苷 40 和 80mg/kg/天组的梗死面积显著减小。柚皮苷改善 IR 后相关的心脏损伤与增加一氧化氮（NO）生物利用度、减少 NO 失活为硝基酪氨酸、放大热休克蛋白 27、70（Hsp27、Hsp70）、β-连环蛋白和增加 p-eNOS/eNOS、p-Akt/Akt 和 p-ERK/ERK 比值有关。此外，IR 诱导的 TNF-α/IKK-β/NF-κB 上调和 JNK 磷酸化也被柚皮苷显著抑制。此外，通过上调 Bcl-2 表达、下调 Bax 和 Caspase-3 表达和减少 TUNEL 阳性，Western blotting 和免疫组织化学分析凋亡信号通路进一步证实了柚皮苷的心脏保护潜力。柚皮苷还使心脏损伤标志物（乳酸脱氢酶和肌酸激酶-MB）、内源性抗氧化活性（超氧化物歧化酶、还原型谷胱甘肽和谷胱甘肽过氧化物酶）和脂质过氧化水平正常化。因此，柚皮苷通过维持心肌结构完整性以及调节 Hsp27、Hsp70、p-eNOS/p-Akt/p-ERK 信号和炎症反应来恢复 IR 损伤。
