Metformin Prevents Progression of Heart Failure in Dogs

Abstract

Background-Some studies have shown that metformin activates AMP-activated protein kinase (AMPK) and has a potent cardioprotective effect against ischemia/reperfusion injury. Because AMPK also is activated in animal models of heart failure, we investigated whether metformin decreases cardiomyocyte apoptosis and attenuates the progression of heart failure in dogs. Methods and Results-Treatment with metformin (10 mol/L) protected cultured cardiomyocytes from cell death during exposure to H 2 O 2 (50 mol/L) via AMPK activation, as shown by the MTT assay, terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling staining, and flow cytometry. Continuous rapid ventricular pacing (230 bpm for 4 weeks) caused typical heart failure in dogs. Both left ventricular fractional shortening and left ventricular end-diastolic pressure were significantly improved in dogs treated with oral metformin at 100 mg · kg Ϫ1 · d Ϫ1 (nϭ8) (18.6Ϯ1.8% and 11.8Ϯ1.1 mm Hg, respectively) compared with dogs receiving vehicle (nϭ8) (9.6Ϯ0.7% and 22Ϯ0.9 mm Hg, respectively). Metformin also promoted phosphorylation of both AMPK and endothelial nitric oxide synthase, increased plasma nitric oxide levels, and improved insulin resistance. As a result of these effects, metformin decreased apoptosis and improved cardiac function in failing canine hearts. Interestingly, another AMPK activator (AICAR) had effects equivalent to those of metformin, suggesting the primary role of AMPK activation in reducing apoptosis and preventing heart failure. Conclusions-Metformin attenuated oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with activation of AMPK. Therefore, metformin may be a potential new therapy for heart failure. (Circulation. 2009;119:2568-2577.)Key Words: AMP-activated protein kinase Ⅲ heart failure Ⅲ metformin Ⅲ nitric oxide M etformin is widely used as an antidiabetic drug with an insulin-sensitizing effect. A large-scale clinical trial (the UK Prospective Diabetes Study [UKPDS] 34) has shown that metformin therapy decreased the risk of cardiovascular death and the incidence of myocardial infarction associated with diabetes mellitus, 1 suggesting that this drug may be useful for patients who have both cardiovascular disease and diabetes mellitus. Eurich and colleagues 2 recently reported the results of a meta-analysis showing that metformin was the only antidiabetic agent to reduce all-cause mortality without causing any harm in patients who had heart failure and diabetes mellitus. These results suggest that a tight link exists between cardiovascular disease and diabetes mellitus and that metformin has a cardioprotective effect. Metformin is known to activate AMP-activated protein kinase (AMPK), [3][4][5] which is expressed in various tissues, including the myocardium, and plays a central role in the regulation of energy metabolism under stress conditions. 6 AMPK is activated by ischemia/reperfusion, 7-9 as well as in hearts with pressure overload hypertrophy 10 and subseque...

Activation of AMP-activated Protein Kinase α1 Alleviates Endothelial Cell Apoptosis by Increasing the Expression of Anti-apoptotic Proteins Bcl-2 and Survivin

“…Our observation is consolidated by a recent study which has also shown that Ca 2ϩ -dependent AMPK activation is required for p65/RelA binding to nuclear DNA in thrombin-stimulated endothelial cells, which is mediated by protein kinase C␦ and p38 MAPK (53). In support of our conclusion, other investigators have noted that AMPK can attenuate apoptotic signaling in biological systems other than the endothelium, such as cardiomyocytes (54,55). Capano and Crompton (56) were one of the first investigators to bridge the gaps between AMPK signaling, p38 MAPK, and apoptotic cell death in ischemic hearts.…”

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

“…Once activated, AMPK promotes catabolic pathways to generate more ATP, and inhibits anabolic pathways, thus allowing for adaptive changes in growth and metabolism under low energy conditions 23. Emerging evidence indicates that AMPK can be activated by metformin in the brain, exerting a neuroprotective role in response to energy depletion through maintaining cellular energy homeostasis,24, 25, 26 promoting mitochondrial biogenesis,27 and increasing brain‐derived neurotrophic factor expression to promote neuronal survival 28. Recently, autophagy has been proposed as a downstream target of AMPK, and AMPK‐induced autophagy activation protects against ischemic injury to peripheral tissue injury29, 30, 31 as well as ischemic brain injury 32.…”

Metformin and heart failure: never say never again

“…Three mechanisms have hitherto been proposed. Based on experimental evidence [30][31][32][33][34][35], the main mechanism appears to be the activation of adenosine monophosphate-activated protein kinase (AMPK) [36]. In experimental models of diabetes and HF, metformin activates AMPK, leading to its increased phosphorylation, which, in turn, results in increased phosphorylation of endothelial nitric oxide synthase (eNOS) [30][31][32][33]35].…”

“…Based on experimental evidence [30][31][32][33][34][35], the main mechanism appears to be the activation of adenosine monophosphate-activated protein kinase (AMPK) [36]. In experimental models of diabetes and HF, metformin activates AMPK, leading to its increased phosphorylation, which, in turn, results in increased phosphorylation of endothelial nitric oxide synthase (eNOS) [30][31][32][33]35]. Thus, plasma and myocardial levels of nitric oxide increase [30,31], ultimately resulting in improved endothelial function, preservation of left ventricular ejection fraction [30,31,33,35], reduced left ventricular dilatation [30,33,35], improved left ventricular end-diastolic pressure [31,35] and also reduced myocardial autophagy [34] and apoptosis [31].…”

“…Furthermore, although some workers have performed multivariate analyses to exclude potential confounding factors [20][21][22][23][24][25][26], the latter have not always been entirely convincingly accounted for. Fifth, and final, most of the information on the mechanisms of action for metformin are currently derived from experimental research [30][31][32][33][34][35]37,39] and need further clinical study.…”