Department of Cardiology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China; Department of Cardiology, the university of Hong Kong-ShenZhen Hospital, Shenzhen 518000, China.
Eur J Pharmacol. 2017 Nov 5;814:335-342. doi: 10.1016/j.ejphar.2017.08.042. Epub 2017 Sep 1.
Although recent findings have suggested that AMP-activated protein kinase (AMPK) exerts inhibitory effects on cardiac remodeling secondary to hypertension, the mechanism and optimal duration of treatment remain unknown. Mice with descending aortic banding (AB) or subjected to sham operation received subcutaneous injection of either AICAR (0.5mggday) or vehicle over 4 week periods. At the end of 4 week treatment, left ventricular (LV) remodeling and function were evaluated with histological analysis and echocardiography. Collagen deposition within the LV myocardium was detected with Masson's trichrome staining. Collagen I, Collagen III, Smad 2, Smad 3, NOX2, NOX4 and Sirt3 (an important antioxidant factor) within the LV tissue were also evaluated. Compared with the sham group, the vehicle-treated AB group exhibited significant elevations in cardiac remodeling and heart failure, characterized by an increase in LV weight relative to body weight, an increase in the area of collagen deposition, an increase in LV end-diastolic diameter, an increase in mitral E inflow velocity to mitral A inflow velocity and increases in the gene expressions of the fibrosis markers Collagen I, III and Smad 2, 3 mRNA and decreases in EF and fractional shortening. AMPK attenuate the cardiac remodeling parameters and improve cardiac function. Moreover, the expressions of NOX2, NOX4 were significantly elevated in vehicle-treated AB group. AMPK was able to significantly inhibit NOX2, NOX4 expression, while activate Sirt3 expression. AMPK significantly attenuated hypertension-induced Ventricular remodeling and dysfunction, which may be mediated by the Sirt3/Oxidative stress signaling pathway.
尽管最近的研究结果表明，AMP 激活的蛋白激酶（AMPK）对高血压引起的心脏重构具有抑制作用，但作用机制和最佳治疗持续时间仍不清楚。接受降主动脉缩窄（AB）或假手术的小鼠接受皮下注射 AICAR（0.5mg/g/天）或载体 4 周。在 4 周治疗结束时，通过组织学分析和超声心动图评估左心室（LV）重构和功能。用 Masson 三色染色检测 LV 心肌内的胶原沉积。还评估了 LV 组织中的胶原 I、胶原 III、Smad 2、Smad 3、NOX2、NOX4 和 Sirt3（一种重要的抗氧化因子）。与假手术组相比，载体处理的 AB 组表现出明显的心脏重构和心力衰竭升高，表现为 LV 重量相对于体重增加，胶原沉积面积增加，LV 舒张末期直径增加，二尖瓣 E 流入速度相对于二尖瓣 A 流入速度增加，纤维化标志物 Collagen I、III 和 Smad 2、3mRNA 的基因表达增加，EF 和分数缩短减少。AMPK 可减轻心脏重构参数并改善心功能。此外，载体处理的 AB 组中 NOX2、NOX4 的表达明显升高。AMPK 能显著抑制 NOX2、NOX4 的表达，同时激活 Sirt3 的表达。AMPK 可显著减轻高血压引起的心室重构和功能障碍，这可能是通过 Sirt3/氧化应激信号通路介导的。
