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

• Published in: Circulation (New York, N.Y.) N.Y.), 2009-05, Vol.119 (19), p.2568-2577
• Main Authors: SASAKI, Hideyuki, ASANUMA, Hoshi, TAKASHIMA, Seiji, SANADA, Shoji, SUGIMACHI, Masaru, KOMAMURA, Kazuo, MOCHIZUKI, Naoki, KITAKAZE, Masafumi, FUJITA, Masashi, TAKAHAMA, Hiroyuki, WAKENO, Masakatsu, ITO, Shin, OGAI, Akiko, ASAKURA, Masanori, KIM, Jiyoong, MINAMINO, Tetsuo
• Format: Article
• Language: English
• Subjects: Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - physiology; Animals; Apoptosis - drug effects; Associated diseases and complications; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiotonic Agents - therapeutic use; Cells, Cultured - drug effects; Cells, Cultured - enzymology; Diabetes. Impaired glucose tolerance; Disease Progression; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dogs; Drug Evaluation, Preclinical; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Fibrosis; Gene Expression Regulation - drug effects; Heart Failure - diagnostic imaging; Heart Failure - drug therapy; Heart Failure - enzymology; Insulin Resistance; Medical sciences; Metformin - therapeutic use; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Natriuretic Peptides - biosynthesis; Natriuretic Peptides - genetics; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type III - biosynthesis; Nitric Oxide Synthase Type III - genetics; Oxidative Stress - drug effects; Phosphorylation - drug effects; Protein Processing, Post-Translational - drug effects; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Rats; Rats, Wistar; Ribonucleotides - pharmacology; Transforming Growth Factor beta1 - biosynthesis; Transforming Growth Factor beta1 - genetics; Ultrasonography; Ventricular Dysfunction, Left - diagnostic imaging; Ventricular Dysfunction, Left - drug therapy; Ventricular Dysfunction, Left - enzymology; Ventricular Dysfunction, Left - genetics
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.108.798561

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. Treatment with metformin (10 micromol/L) protected cultured cardiomyocytes from cell death during exposure to H2O2 (50 micromol/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 x kg(-1) x 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. 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.