title: Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase-endothelial nitric oxide synthase pathway in rats.
abstract: 1. Metformin is an activator of AMP-activated protein kinase (AMPK). Recent studies suggest that pharmacological activation of AMPK inhibits cardiac hypertrophy. In the present study, we examined whether long-term treatment with metformin could attenuate ventricular hypertrophy in a rat model. The potential involvement of nitric oxide (NO) in the effects of metformin was also investigated. 2. Ventricular hypertrophy was established in rats by transaortic constriction (TAC). Starting 1 week after the TAC procedure, rats were treated with metformin (300 mg/kg per day, p.o.), N(G)-nitro-L-arginine methyl ester (L-NAME; 50 mg/kg per day, p.o.) or both for 8 weeks prior to the assessment of haemodynamic function and cardiac hypertrophy. 3. Cultured cardiomyocytes were used to examine the effects of metformin on the AMPK-endothelial NO synthase (eNOS) pathway. Cells were exposed to angiotensin (Ang) II (10⁻⁶ mol/L) for 24 h under serum-free conditions in the presence or absence of metformin (10⁻³ mol/L), compound C (10⁻⁶ mol/L), L-NAME (10⁻⁶ mol/L) or their combination. The rate of incorporation of [³H]-leucine was determined, western blotting analyses of AMPK-eNOS, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) were undertaken and the concentration of NO in culture media was determined. 4. Transaortic constriction resulted in significant haemodynamic dysfunction and ventricular hypertrophy. Myocardial fibrosis was also evident. Treatment with metformin improved haemodynamic function and significantly attenuated ventricular hypertrophy. Most of the effects of metformin were abolished by concomitant L-NAME treatment. L-NAME on its own had no effect on haemodynamic function and ventricular hypertrophy in TAC rats. 5. In cardiomyocytes, metformin inhibited AngII-induced protein synthesis, an effect that was suppressed by the AMPK inhibitor compound C or the eNOS inhibitor L-NAME. The improvement in cardiac structure and function following metformin treatment was associated with enhanced phosphorylation of AMPK and eNOS and increased NO production. 6. The findings of the present study indicate that long-term treatment with metformin could attenuate ventricular hypertrophy induced by pressure overload via activation of AMPK and a downstream signalling pathway involving eNOS-NO.
authors.affiliation: Department of Cardiology, First Affiliated Hospital of Sun Yat-sen, Guangzhou, China.
authors.forename: Cheng-Xi
authors.initials: CX
authors.lastname: Zhang
authors.forename: Si-Nian
authors.initials: SN
authors.lastname: Pan
authors.forename: Rong-Sen
authors.initials: RS
authors.lastname: Meng
authors.forename: Chao-Quan
authors.initials: CQ
authors.lastname: Peng
authors.forename: Zhao-Jun
authors.initials: ZJ
authors.lastname: Xiong
authors.forename: Bao-Lin
authors.initials: BL
authors.lastname: Chen
authors.forename: Guang-Qin
authors.initials: GQ
authors.lastname: Chen
authors.forename: Feng-Juan
authors.initials: FJ
authors.lastname: Yao
authors.forename: Yi-Li
authors.initials: YL
authors.lastname: Chen
authors.forename: Yue-Dong
authors.initials: YD
authors.lastname: Ma
authors.forename: Yu-Gang
authors.initials: YG
authors.lastname: Dong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases