Exendin-4对苯肾上腺素诱导的心肌肥厚的影响及作用机制  

Effect of Treatment with Exendin-4 on Cardiac Hypertrophy Induced by Phenylephrine

作　　者：周越[1] 何昕[2] 黄艺仪[3] 陈艺莉[1] 何建桂[1] 

机构地区：[1]中山大学附属第一医院心内科,广东广州510080 [2]中山大学中山医学院,广东广州510080 [3]中山大学附属第一医院急诊科,广东广州510080

出　　处：《中山大学学报（医学科学版）》2016年第1期40-47,共8页Journal of Sun Yat-Sen University:Medical Sciences

基　　金：广东省科技计划项目(2012B031800386);广东省自然科学基金(2014A030313019)

摘　　要：【目的】探讨胰高血糖素样肽-1类似物exendin-4对苯肾上腺素诱导的心肌肥厚的影响及作用机制。【方法】用exendin-4、exendin9-39及Compound C预处理无血清饥饿状态的原代心肌细胞30min后,予以苯肾上腺素共培养24h,再以Q-PCR检测心肌细胞内肥厚标志物ANP,BNP,β-MHC的m RNA水平,Image-Pro Plus软件测量心肌细胞表面积,免疫荧光技术观察心肌细胞形态的变化及Western-Blotting检测相关信号通路分子的改变。【结果】exendin-4处理能够显著减轻苯肾上腺素诱导的心肌细胞肥厚标志物的表达及心肌细胞面积的增大(P<0.05),GLP-1R受体特异性拮抗剂能抑制exendin-4的抗心肌肥厚作用(P<0.05)。exendin-4处理能明显上调AMPK的蛋白磷酸化水平及下调Erk1/2蛋白磷酸化水平(P<0.05),但不能改变p38蛋白磷酸化水平。使用AMPK抑制剂Compound C能明显抑制exendin-4处理的效应(P<0.05),且能抑制m TOR及p70S6K蛋白磷酸化(P<0.05)。【结论】exendin-4通过与GLP-1R相互作用发挥其抗心肌肥厚作用,且Erk1/2信号分子及AMPK/m TOR/p70S6K信号通路参与exendin-4抗心肌肥厚过程。【Objective】 The purpose of this study was to investigate the in vitro effect of exendin-4 on cardiomyocytes hypertrophy induced by phenylephrine（PE） and to clarify the mechanism underlying this process. 【Methods】 Serum-starved neonatal rat ventricular cardiomyocytes（NRVCs） were pretreated with exedin-4, exendin9-39 or Compound C, then which was co-incubated with phenylephrine 24 h. The m RNA expression level of cardiac hypertrophic markers（ANP, BNP, and β-MHC） was analyzed by Q-PCR.The surface area of cardiomyocyes was measured by Image-Pro Plus software and the morphology of cardiomyocytes treated with exendin-4 was exhibited by immunofluorescence staining. The involvement of signaling pathways underlying the process was determined by Western blotting. 【Result】 Our data showed that exendin-4 treatment notably decreased the m RNA expression level of cardiac hypertrophic markers induced by PE and the enlargement of cell surface area（P〈0.05）, which could be reversed by glucagon-like peptide-1 receptor（GLP-1R） antagonist exendin9-39（P〈0.05）. Exendin-4 treatment also upregulated the phosphorylation level of AMPK and downregulated the phosphorylation level of Erk1 / 2（P〈0.05）, but not p38. Furthermore,pretreatment with AMPK inhibitor Compound C could significantly eliminated the anti-hypertrophic effect of exendin-4（P〈0.05） and upregulated the phosphorylation level of m TOR and p70S6K（P〈0.05）. 【Conclusion】 Exendin-4 could attenuate cardiac hypertrophy induced by phenylephrine via GLP-1 receptor. Both Erk1 / 2 and AMPK / m TOR / p70S6 K signal pathways were involved in the antihypertrophic effect of exendin-4.

关 键 词：EXENDIN-4 心肌肥厚 GLP-1R受体 ERK1/2 AMPK Compound C 

分 类 号：Q2[生物学—细胞生物学]