Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase.
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.


RESULTS
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.


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.
Department of Cardiovascular Medicine, National Cardiovascular Center, Suita, Osaka, Japan.
Hideyuki
H
Sasaki
Hiroshi
H
Asanuma
Masashi
M
Fujita
Hiroyuki
H
Takahama
Masakatsu
M
Wakeno
Shin
S
Ito
Akiko
A
Ogai
Masanori
M
Asakura
Jiyoong
J
Kim
Tetsuo
T
Minamino
Seiji
S
Takashima
Shoji
S
Sanada
Masaru
M
Sugimachi
Kazuo
K
Komamura
Naoki
N
Mochizuki
Masafumi
M
Kitakaze
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D018450:Disease Progression; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D007333:Insulin Resistance; D008687:Metformin / Q000627:therapeutic use*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D045265:Natriuretic Peptides / Q000096:biosynthesis / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics
D002316:Cardiotonic Agents; D045265:Natriuretic Peptides; D011720:Pyrazoles; D011743:Pyrimidines; D012265:Ribonucleotides; D053773:Transforming Growth Factor beta1; C516138:dorsomorphin; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide