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.

Resveratrol, an activator of SIRT1, upregulates AMPK and improves cardiac function in heart failure

“…Our findings have broad implications because changes in AMPK expression levels are not limited to end-stage heart failure due to ischemic cardiomyopathy, but also play a role in hypertrophic cardiomyopathy (Turdi et al, 2011;Zhang et al, 2011b), diabetic hearts, and aging hearts, and resveratrol treatment has been found to be beneficial under all of these conditions (Thirunavukkarasu et al, 2007;Alcendor et al, 2007;Sulaiman et al, 2010). Therefore, our study might have profound implications for the treatment of heart failure and other cardiac disorders, and suggests that diets rich in resveratrol will prove beneficial in this disease.…”

Metformin: From Mechanisms of Action to Therapies

“…AMPK is a known inhibitor of cardiac hypertrophy via the negative regulation of protein synthesis (via mTOR inhibition) and of gene transcription including mitogen-activated protein kinase and calcineurin-nuclear factor of activated T cells pathways (Horman et al, 2012). In agreement with the antihypertrophic action of AMPK, metformin inhibits cardiac hypertrophy in a rat model of pressure overload (transverse aortic constriction) (Zhang et al, 2011). A very recent publication has reported that metformin protects against transverse aortic constriction-mediated cardiac hypertrophy independently of AMPK .…”

AMPK activation—protean potential for boosting healthspan

“…In rodent studies of cardiac pressure overload, concurrent treatment with AICAR, metformin, or berberine has reduced ventricular hypertrophy; conversely, mice which are genetically deficient in AMPK-α2 or in LKB1 expression are more prone to ventricular hypertrophy in the context of overload (Fu et al 2011;Beauloye et al 2011;Benes et al 2011;Zhang et al 2011aZhang et al , 2008bLi et al 2007;Hong et al 2002Hong et al , 2003. The protection afforded by AMPK in this regard reflects not only an effect on cardiomyocyte hypertrophy, but also an antifibrotic effect (Beauloye et al 2011;Zhang et al 2008b).…”

“…The protection afforded by AMPK in this regard reflects not only an effect on cardiomyocyte hypertrophy, but also an antifibrotic effect (Beauloye et al 2011;Zhang et al 2008b). Although the downregulatory impact of AMPK on protein synthesis might play some role in this effect, there is evidence that increased eNOS activity also plays a prominent role; (Zhang et al 2011a) indeed, it is well established that effective NO activity tends to prevent cardiac hypertrophy (Massion and Balligand 2007).…”