Effect of carvedilol on cardiomyocyte apoptosis in a rat model of myocardial infarction: a role for toll-like receptor 4.
Effect of carvedilol on cardiomyocyte apoptosis in a rat model of myocardial infarction: a role for toll-like receptor 4.
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DOI：
10.4103/0253-7613.117729
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发表时间：
2013-09
影响因子：
2.4
通讯作者：
Wu C
中科院分区：
文献类型：
--
作者：
Liu Q;Zhang J;Xu Y;Huang Y;Wu C
Toll样受体4（TLR 4）在心肌梗死（MI）诱导的心肌细胞凋亡中起重要作用，卡维地洛具有抗凋亡作用。我们假设这种药物的作用部分是通过TLR 4信号通路介导的。将48只大鼠随机分为假手术组（n = 8）、心肌梗死组（n = 10）和3个卡维地洛治疗组（n = 30、2 mg/kg、10 mg/kg和30 mg/kg）。假手术组和心肌梗死组给予溶媒，卡维地洛组给予不同剂量卡维地洛，直接灌胃7 d。在给药或赋形剂的第4天，通过结扎冠状动脉左前降支制备MI模型。心肌梗死后第3天，采用TdT-UTP缺口末端法检测心肌细胞凋亡，免疫组化法检测心肌细胞凋亡相关蛋白Bax、Bcl-2、TLR 4和核因子-κB（NF-κB）的表达。卡维地洛以剂量依赖性方式改善MI诱导的细胞凋亡。卡维地洛还可降低心肌梗死后Bax/Bcl-2比值、TLR 4和NF-κB的表达。TLR 4水平与细胞凋亡程度及Bcl-2/Bcl-2比值密切相关。短期应用卡维地洛可能通过抑制梗死诱导的TLR 4和NF-κB的过度表达，减轻梗死心肌细胞凋亡。
Toll-like receptor 4 (TLR4) is crucial in cardiomyocyte apoptosis induced by myocardial infarction (MI) and carvedilol has been reported to have anti-apoptotic effects. We hypothesized that the effects of this agent are in part mediated through TLR4 signaling pathways. A total of 48 rats were randomized to the following groups before surgery: sham-operated group (n = 8), MI group (n = 10) and three carvedilol-treatment groups (n = 30, 2 mg/kg, 10 mg/kg and 30 mg/kg). Sham and MI groups were given vehicle and carvedilol groups received different dose carvedilol, by direct gastric gavage for 7 days. On the 4th day of drug or vehicle administration, MI model was produced by ligating the left anterior descending coronary artery. On day 3 after MI, apoptosis was assessed by TdT-UTP nick-end assay; the levels of expression of Bax, Bcl-2, TLR4 and nuclear factor-κB (NF-κB) in infarcted myocardium were analyzed by immunohistochemistry. Carvedilol ameliorated MI-induced apoptosis in a dose-dependent manner. In parallel, carvedilol also decreased the ratio of Bax to Bcl-2, the expression of TLR4 and NF-κB induced by MI. The extent of apoptosis and Bax-Bcl-2 ratio was strongly correlated with the TLR4 levels. This study suggests that the short-term administration of carvedilol can significantly alleviate cardiomyocyte apoptosis in the infarcted myocardium probably by inhibiting the excessive expression of TLR4 and NF-κB induced by infarction.
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