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基于AMPK/SIRT1/PGC-1α信号通路研究香青兰总黄酮对大鼠心肌缺血再灌注损伤的保护机制
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| 篇名： | 基于AMPK/SIRT1/PGC-1α信号通路研究香青兰总黄酮对大鼠心肌缺血再灌注损伤的保护机制 |
| TITLE： | Study on Protective Mechanism of Dracocephalum moldavica Total Flavonoids against Myocardial Ischemia- reperfusion Injury in Rats Based on AMPK/SIRT 1/PGC-1α Signaling Pathway |
| 摘要： | 目的：研究香青兰总黄酮（TFDM）对腺苷酸活化蛋白激酶（AMPK）/沉默信息调节因子1（SIRT1）/过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1α）信号通路的影响，探究其保护大鼠心肌缺血再灌注损伤（MIRI）的作用机制。方法：将50只健康雄性SD大鼠随机分为假手术组、模型组、TFDM组[60mg/（kg·d），以提取物计]、CompoundC+TFDM组[灌胃60mg/（kg·d）TFDM+再灌注前15min尾静脉注射250μg/kgCompoundC（AMPK抑制剂）]、EX-527+TFDM组[灌胃60mg/（kg·d）TFDM+再灌注前20min腹腔注射5mg/kgEX-527（SIRT1抑制剂）]，每组10只。每天灌胃给药1次，连续7d。末次灌胃给药后，假手术组大鼠行假手术，其余4组大鼠均采用结扎冠状动脉左前降支缺血30min、再灌注2h构建MIRI模型。再灌注结束后，采用苏木精-伊红染色法观察大鼠心肌组织病理学变化；采用反相高效液相色谱法测定其心肌组织中腺苷三磷酸（ATP）、腺苷二磷酸（ADP）、腺苷一磷酸（AMP）及烟酰胺腺嘌呤二核苷酸（NAD+）的含量；采用实时荧光定量-聚合酶链式反应法检测大鼠心肌组织中AMPK、SIRT1和PGC-1αmRNA表达水平；采用Westernblotting法检测大鼠心肌组织中AMPK蛋白的磷酸化水平和SIRT1、PGC-1α蛋白表达水平。结果：与假手术组比较，模型组大鼠心肌纤维排列紊乱、横向条纹消失，细胞肿胀破裂、坏死，细胞核变形移位；心肌组织中ATP、NAD+含量和AMPK、SIRT1、PGC-1αmRNA表达水平以及SIRT1、PGC-1α蛋白表达水平均显著降低（P＜0.05或P＜0.01），ADP、AMP含量及AMPK蛋白的磷酸化水平均显著升高（P＜0.01）。与模型组比较，TFDM组大鼠心肌病理学形态明显改善；心肌组织中ATP、NAD+含量和AMPK、SIRT1、PGC-1αmRNA表达水平以及AMPK蛋白的磷酸化水平和SIRT1、PGC-1α蛋白表达水平均显著升高（P＜0.05或P＜0.01），ADP、AMP含量均显著降低（P＜0.01）。与TFDM组比较，CompoundC+TFDM组和EX-527+TFDM组大鼠上述指标的改善作用均被逆转（P＜0.05或P＜0.01）。结论：TFDM可能是通过激活AMPK/SIRT1/PGC-1α信号通路，调节能量代谢，从而发挥其对心肌的保护作用。 |
| ABSTRACT： | OBJECTIVE：To s tudy the effects of Dracocephalum moldavica total flavonoids （TFDM）on AMPK/SIRT 1/PGC-1α signaling pathway ，and to explore the mechanism of its protective effect on myocardial ischemia reperfusion injury （MIRI）rats. METHODS：Totally 50 healthy male SD rats were randomly divided into sham operation group ，model group ，TFDM group [ 60 mg/（kg·d），by extract] ，Compound C+TFDM group [ig administration of 60 mg/（kg·d）TFDM+intravenous injection of 250 μg/kg Compound C（AMPK inhibitor ）via tail vein 15 min before reperfusion] ，EX-527+TFDM group [ig administration of 60 mg/ （kg·d）TFDM+ip injection of 5 mg/kg EX- 527（SIRT1 inhibitor）20 min before reperfusion] ，with 10 rats in each group. They were given relevant medicine intragastrically ，once a day ，for consecutive 7 days. After last ig administration ，sham operation group underwent sham operation ，other 4 groups were established MIRI model by ligating left anterior descending coronary artery ， ischemia for 30 min and reperfusion for 2 h. After reperfusion ，the myocardial histopathological changes were observed by HE staining；RP-HPLC method was used to determine the contents of ATP ，ADP，AMP and NAD + in cardiac tissue. mRNA expressions of AMPK ，SIRT1 and PGC- 1α were detected by quantitative real-time PCR assay. Western blotting assay was the expressions of SIRT 1 and PGC- 1α protein in myocardium. RESULTS： Compared with sham operation group ， model group showed myocardial fib ers arranged disorder and horizontal stripes disappearance ，cell swelling burst and necrosis ，and nuclei deformation displacement ；the contents of ATP and NAD+，mRNA expression of AMPK ，SIRT1 and PGC- 1α，protein expression of SIRT 1 and PGC- 1α in cardiac tissue were decreased significantly （P＜0.05 or P＜0.01）；the contents of ADP and AMP ，the phosphorylation level of AMPK protein were increased significantly （P＜0.01）. Compared with model group ，myocardial pathological morphology were improved significantly in TFDM group ；the contents of ATP and NAD + in cardiac tissue ，mRNA expression of AMPK ，SIRT1 and PGC- 1α，the phosphorylation level of AMPK protein ，the protein expression of SIRT 1 and PGC- 1α were increased significantly（P＜0.05 or P＜ 0.01），while the contents of ADP and AMP were decreased significantly （P＜0.01）. Compared with TFDM group ，improvement effects of Compound C + TFDM group and EX- 527 + TFDM group on above indexes were reversed （P＜0.05 or P＜0.01）. CONCLUSIONS：TFDM may play a protective role on myocardium by activating AMPK/SIRT 1/PGC-1α signaling pathway and regulating energy metabolism. |
| 期刊： | 2021年第32卷第03期 |
| 作者： | 赵云丽，袁勇，马晓莉，黄川生，文志萍，郭新红，王新春 |
| AUTHORS： | ZHAO Yunli，YUAN Yong，MA Xiaoli，HUANG Chuansheng，WEN Zhiping，GUO Xinhong，WANG Xinchun |
| 关键字： | 香青兰总黄酮；能量代谢；腺苷酸活化蛋白激酶 ；沉默信息调节因子 1；过氧化物酶体增殖物激活受体 γ辅激活因子 1α； |
| KEYWORDS： | Dracocephalum moldavica total flavonoids ；Energy metabolism ；AMPK；SIRT1；PGC-1α；Mechanism |
| 阅读数： | 579 次 |
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