二甲双胍通过激活AMP依赖的蛋白激酶改善压力引起的心肌肥厚的研究

Metformin protects against pressure overload-induced cardiac hypertrophy by activating adenosine 5’-monophosphate-activated protein kinase

目的探讨二甲双胍(Met)激活AMP依赖的蛋白激酶(AMPK)减轻炎症反应在压力负荷引起的心肌肥厚中的作用。方法用主动脉弓缩窄术(TAC)制备压力负荷引起的心肌肥厚模型。将模型小鼠随机分为模型组、对照组和实验组,每组10只;另取10只小鼠进行相同手术,但只穿线不结扎主动脉作为假手术组。模型组和假手术组均给予0.9%Na Cl;对照组给予腹腔注射200mg·kg^(-1)Met 0.5 mL;实验组给予腹腔注射200 mg·kg^(-1)Met 0.5 mL+20mg·kg^(-1)Compound C 0.5 mL。4组小鼠从TAC术后第1天开始注射,每周3次,持续6周。用小动物超声检测射血分数(EF)和短轴缩短率(FS),用蛋白质印迹法检测心肌组织中磷酸化AMPK(p-AMPK)和磷酸化乙酰辅酶A羧化酶(p-ACC)蛋白的表达水平。结果实验组、对照组、模型组和假手术组的EF分别为(41.79±3.75)%,(61.74±2.87)%,(42.63±4.06)%和(75.86±3.92)%,FS分别为(26.91±3.58)%,(36.79±2.93)%,(27.25±3.35)%和(43.58±4.16)%,p-AMPK相对表达量分别为0.37±0.11,0.89±0.05,0.53±0.04和1.13±0.03,p-ACC相对表达量分别为0.47±0.07,0.95±0.04,0.51±0.05和1.09±0.02。对照组的上述指标与实验组和模型组比较,差异均有统计学意义(均P <0.01)。结论 Met通过激活AMPK来抑制心脏炎症反应,从而减轻小鼠压力负荷引起的心肌肥厚。

Objective To investigate the effect of adenosine 5’-monophosphate-activated protein kinase(AMPK) activation by metformin(Met) on inhibiting inflammatory in pressure overload induced cardiac hypertrophy.Methods The model of pressure overload induced cardiac hypertrophy was established by transverse aortic constriction(TAC).The model mice were randomly divided into model,control and experimental groups with 10 mice per group.Another 10 mice were underwent for the same operation,but the aorta was not ligated as the sham-operation group.The model and sham-operation groups were treated with 0.9% NaCl.The control group was intraperitoneally injected200 mg·kg^(-1) Met 0.5 mL.The experimental group was intraperitoneally injected 200 mg·kg^(-1) Met 0.5 mL+20 mg·kg^(-1) Compound C 0.5 mL.Mice were injected three times a week from the first day after TAC for 6 weeks.The ejection fraction(EF) and fractional shortening(FS)were measured with ultrasonic apparatus.The protein expression of phosphorylation(p-) of AMPK and acetyl Co A carboxylase(ACC) was measured by Western Blot.Results The EF values in experimental,control,model and sham-operation groups were(41.79±3.75) %,(61.74±2.87) %,(42.63±4.06) % and(75.86±3.92) %,the FS values were(26.91±3.58) %,(36.79±2.93) %,(27.25±3.35) % and(43.58±4.16) %,the relative expression levels of p-AMPK were 0.37±0.11,0.89±0.05,0.53±0.04 and 1.13±0.03,the relative expression levels of p-ACC were 0.47±0.07,0.95±0.04,0.51±0.05 and 1.09±0.02,respectively.The above indexes of the control group were significantly different from those in the experimental and model groups(all P <0.01).Conclusion Met reduced pressure overload-induced cardiac hypertrophy by inhibiting inflammatory response via AMPK activation.