Published Online
on May 4, 2009

A more recent version of this article appeared on May 19, 2009

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Submitted on August 23, 2007
Accepted on February 24, 2009

Metformin Prevents Progression of Heart Failure in Dogs. Role of AMP-Activated Protein Kinase

Hideyuki Sasaki MD, Hiroshi Asanuma MD, PhD, Masashi Fujita MD, PhD, Hiroyuki Takahama MD, PhD, Masakatsu Wakeno MD, PhD, Shin Ito MD, Akiko Ogai BS, Masanori Asakura MD, PhD, Jiyoong Kim MD, Tetsuo Minamino MD, PhD, Seiji Takashima MD, PhD, Shoji Sanada MD, PhD, Masaru Sugimachi MD, PhD, Kazuo Komamura MD, PhD, Naoki Mochizuki MD, PhD, and Masafumi Kitakaze MD, PhD^*

From the Department of Cardiovascular Medicine, National Cardiovascular Center (H.S., H.A., H.T., M.W., S.I., A.O., M.A., J.K., K.K., M.K.) and Departments of Structural Analysis (H.S., H.T., M.W., S.I., N.M.) and Cardiovascular Dynamics (M.S., K.K.), Research Institute, National Cardiovascular Center, Suita, Osaka; Departments of Bioregulatory Medicine (H.S., H.T., M.W., S.I., N.M.) and Cardiovascular Medicine (M.F., T.M., S.T., S.S.), Osaka University Graduate School of Medicine, Suita, Osaka, Japan; and Department of Emergency Room Medicine, Kinki University School of Medicine, Osaka-Sayama (H.A.), Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: kitakaze{at}zf6.so-net.ne.jp.

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 µmol/L) protected cultured cardiomyocytes from cell death during exposure to H₂O₂ (50 µmol/L) via AMPK activation, as shown by the MTT assay, terminal deoxynucleotidyl transferase–mediated 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^-1 · d^-1 (n=8) (18.6±1.8% and 11.8±1.1 mm Hg, respectively) compared with dogs receiving vehicle (n=8) (9.6±0.7% and 22±0.9 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.

Key words: AMP-activated protein kinase • heart failure • metformin • nitric oxide

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Clinical Summaries
Circulation 2009 119: 2537-2538. [Extract] [Full Text]

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