College of Pharmacy, Xinjiang Medical University, No. 393 Xinyi Road, Urumqi, 830054, China.
Xinjiang Institute of Materia Medica, No. 140 Xinhua South Road, Urumqi, China.
Sci Rep. 2018 Nov 30;8(1):17491. doi: 10.1038/s41598-018-35726-4.
We previously demonstrated the cardio-protection mediated by the total flavonoid extracted from Dracocephalum moldavica L. (TFDM) following myocardial ischemia reperfusion injury (MIRI). The present study assessed the presence and mechanism of TFDM-related cardio-protection on MIRI-induced apoptosis in vivo. Male Sprague-Dawley rats experienced 45-min ischemia with 12 h of reperfusion. Rats pretreated with TFDM (3, 10 or 30 mg/kg/day) were compared with Sham (no MIRI and no TFDM), MIRI (no TFDM), and Positive (trapidil tablets, 13.5 mg/kg/day) groups. In MIRI-treated rats, high dose-TFDM (H-TFDM) pre-treatment with apparently reduced release of LDH, CK-MB and MDA, enhanced the concentration of SOD in plasma, and greatly reduced the infarct size, apoptotic index and mitochondrial injury. H-TFDM pretreatment markedly promoted the phosphorylation of PI3K, Akt, GSK-3β and ERK1/2 in comparison with the MIRI model group. Western blot analysis after reperfusion also showed that H-TFDM decreased release of Bax, cleaved caspase-3, caspase-7 and caspase-9, and increased expression of Bcl-2 as evident by the higher Bcl-2/Bax ratio. TFDM cardio-protection was influenced by LY294002 (PI3K inhibitor) and PD98059 (ERK1/2 inhibitor). Taken together, these results provide convincing evidence of the benefit of TFDM pretreatment due to inhibited myocardial apoptosis as mediated by the PI3K/Akt/GSK-3β and ERK1/2 signaling pathways.
我们之前证明了从Dracocephalum moldavica L. 中提取的总黄酮（TFDM）在心肌缺血再灌注损伤（MIRI）后具有心脏保护作用。本研究评估了 TFDM 相关心脏保护作用在体内 MIRI 诱导的细胞凋亡中的存在和机制。雄性 Sprague-Dawley 大鼠经历 45 分钟缺血和 12 小时再灌注。用 TFDM（3、10 或 30mg/kg/天）预处理的大鼠与 Sham（无 MIRI 和无 TFDM）、MIRI（无 TFDM）和阳性（曲普立啶片，13.5mg/kg/天）组进行比较。在 MIRI 处理的大鼠中，高剂量 TFDM（H-TFDM）预处理明显降低 LDH、CK-MB 和 MDA 的释放，增加血浆中超氧化物歧化酶的浓度，并大大减少梗塞面积、细胞凋亡指数和线粒体损伤。与 MIRI 模型组相比，H-TFDM 预处理明显促进了 PI3K、Akt、GSK-3β 和 ERK1/2 的磷酸化。再灌注后的 Western blot 分析还表明，H-TFDM 降低了 Bax、切割的 caspase-3、caspase-7 和 caspase-9 的释放，并增加了 Bcl-2 的表达，Bcl-2/Bax 比值升高。TFDM 的心脏保护作用受到 LY294002（PI3K 抑制剂）和 PD98059（ERK1/2 抑制剂）的影响。综上所述，这些结果提供了令人信服的证据，证明 TFDM 预处理通过抑制 PI3K/Akt/GSK-3β 和 ERK1/2 信号通路介导的心肌细胞凋亡，具有心脏保护作用。
