Department of Pharmacology, Kalpana Chawla Government Medical College, Karnal, Haryana, 132001, India; Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029, India.
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029, India.
Eur J Pharmacol. 2020 Sep 15;883:173389. doi: 10.1016/j.ejphar.2020.173389. Epub 2020 Jul 22.
Pharmacological strategies aimed at co-activating peroxisome proliferator-activated receptor-gamma (PPAR-γ)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway have shown promising results in alleviating myocardial injury. The aim of the study was to evaluate the role of chrysin, a PPAR-γ agonist, in ischemia-reperfusion (IR)-induced myocardial infarction (MI) in rats and to explore the molecular mechanism driving this activity. To evaluate this hypothesis, chrysin (60 mg/kg, orally), PPAR-γ antagonist (GW9662, 1 mg/kg, intraperitoneally), or both were administered to rats for 28 days. On the 29th day, one-stage ligation of left anterior descending coronary artery for 45 min followed by 60 min of reperfusion was performed. Chrysin significantly decreased infarct size and improved cardiac functions following IR-induced MI. This improvement was corroborated by augmented PPAR-γ/Nrf2 expression as confirmed by immunohistochemistry and western blotting analysis. Chrysin exhibited strong anti-oxidant property as demonstrated by increased GSH and CAT levels and decreased 8-OHdG and TBARS levels. Our findings also imply that chrysin significantly inhibited inflammatory response as validated by decreased NF-κB, IKK-β, CRP, TNF-α and MPO levels. In addition, chrysin decreased TUNEL/DAPI positivity, a marker of apoptotic response and normalized cardiac injury markers. The histopathological and ultrastructural analysis further supported the functional and biochemical outcomes, showing preserved myocardial architecture. Intriguingly, co-administration with GW9662 significantly diminished the cardioprotective effect of chrysin as demonstrated by depressed myocardial function, decreased PPAR-γ/Nrf2 expression and increased oxidative stress. In conclusion, the present study demonstrates that co-activation of PPAR-γ/Nrf2 by chrysin may be crucial for its cardioprotective effect.
旨在共同激活过氧化物酶体增殖物激活受体-γ（PPAR-γ）/核因子红细胞 2 相关因子 2（Nrf2）途径的药理学策略已显示出在减轻心肌损伤方面有可喜的结果。本研究旨在评估 PPAR-γ 激动剂白杨素在大鼠缺血再灌注（IR）诱导的心肌梗死（MI）中的作用，并探讨驱动这种活性的分子机制。为了评估这一假设，给大鼠给予白杨素（60mg/kg，口服）、PPAR-γ 拮抗剂（GW9662，1mg/kg，腹腔内注射）或两者共 28 天。在第 29 天，对大鼠进行左前降支冠状动脉一期结扎 45min 后再灌注 60min。白杨素显著减少 IR 诱导的 MI 后的梗死面积并改善心功能。免疫组织化学和 Western blot 分析证实，PPAR-γ/Nrf2 表达增加证实了这一改善。白杨素表现出很强的抗氧化特性，表现为 GSH 和 CAT 水平增加，8-OHdG 和 TBARS 水平降低。我们的研究结果还表明，白杨素显著抑制了炎症反应，如 NF-κB、IKK-β、CRP、TNF-α 和 MPO 水平降低所证实的那样。此外，白杨素减少了 TUNEL/DAPI 阳性，这是一种凋亡反应的标志物，并使心脏损伤标志物正常化。组织病理学和超微结构分析进一步支持了功能和生化结果，显示出保存的心肌结构。有趣的是，与 GW9662 共同给药显著减弱了白杨素的心脏保护作用，表现为心肌功能下降、PPAR-γ/Nrf2 表达减少和氧化应激增加。总之，本研究表明，白杨素共同激活 PPAR-γ/Nrf2 可能是其心脏保护作用的关键。
