Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
Eur J Pharm Sci. 2018 Aug 30;121:243-250. doi: 10.1016/j.ejps.2018.05.023. Epub 2018 May 31.
The potential mechanism of penehyclidine hydrochloride (PHC) against myocardial ischemia-reperfusion (I/R) injury has not been fully elucidated. The aim of the present study was to reveal whether mitochondrial dynamics, apoptosis, and MAPKs were involved in the cardioprotective effect of this drug on myocardial I/R injury.
Ninety healthy adult male Wistar rats were separately pretreated with normal saline (0.9%); PHC; and signal pathway blockers of MAPKs, Drp1, and Bcl-2. Coronary artery ligation and subsequent reperfusion were performed to induce myocardial I/R injury. Echocardiography was performed. Myocardial enzymes and oxidative stress markers were detected. Myocardial cell apoptotic rates and infarct sizes were measured. Mitochondrial function was evaluated. Expression levels of MAPKs, mitochondria regulatory proteins (Drp1, Mfn1/2), and apoptosis-related proteins (Bcl-2, Bax) were determined.
PHC pretreatment improved myocardial abnormalities (dysfunction, injury, infarct size, and apoptotic rate), mitochondrial abnormalities (dysfunction and fission), and excessive oxidative stress and inhibited the activities of p38MAPK and JNK signal pathways in rats with myocardial I/R injury (P < 0.05). Additionally, p38MAPK and JNK blockers (SB239063 and SP600125, respectively) had an effect on rats same as that of PHC. Although Drp1 blocker (Mdivi-1) showed a similar cardioprotective effect (P < 0.05), it did not affect the expression of MAPKs and apoptosis-related proteins (P > 0.05). In addition, Bcl-2 blocker (ABT-737) caused a high expression of Drp1 and a low expression of Mfn1/2 (P < 0.05).
PHC regulated mitochondrial dynamics and apoptosis through p38MAPK and JNK signal pathways and provided cardioprotection in rats with myocardial I/R injury.
盐酸戊乙奎醚（PHC）对抗心肌缺血再灌注（I/R）损伤的潜在机制尚未完全阐明。本研究旨在揭示线粒体动力学、细胞凋亡和 MAPKs 是否参与了该药对心肌 I/R 损伤的心脏保护作用。
90 只健康成年雄性 Wistar 大鼠分别用生理盐水（0.9%）；PHC；以及 MAPKs、Drp1 和 Bcl-2 的信号通路阻滞剂预处理。通过冠状动脉结扎和随后的再灌注来诱导心肌 I/R 损伤。进行超声心动图检查。检测心肌酶和氧化应激标志物。测量心肌细胞凋亡率和梗死面积。评估线粒体功能。测定 MAPKs、线粒体调节蛋白（Drp1、Mfn1/2）和凋亡相关蛋白（Bcl-2、Bax）的表达水平。
PHC 预处理改善了心肌异常（功能障碍、损伤、梗死面积和凋亡率）、线粒体异常（功能障碍和分裂）以及过度氧化应激，并抑制了 p38MAPK 和 JNK 信号通路在心肌 I/R 损伤大鼠中的活性（P<0.05）。此外，p38MAPK 和 JNK 阻滞剂（SB239063 和 SP600125）对大鼠的作用与 PHC 相同。虽然 Drp1 阻滞剂（Mdivi-1）表现出相似的心脏保护作用（P<0.05），但它不影响 MAPKs 和凋亡相关蛋白的表达（P>0.05）。此外，Bcl-2 阻滞剂（ABT-737）导致 Drp1 表达增加和 Mfn1/2 表达降低（P<0.05）。
PHC 通过 p38MAPK 和 JNK 信号通路调节线粒体动力学和细胞凋亡，为心肌 I/R 损伤大鼠提供心脏保护作用。
