Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening.
BACKGROUND
In the majority of studies, metformin has been demonstrated to cardioprotect diabetic patients, the mechanism of which is unclear. We hypothesized that metformin cardioprotects the ischemic heart through the Akt-mediated inhibition of mitochondrial permeability transition pore (mPTP) opening.


METHODS
Isolated perfused hearts from normoglycemic Wistar or from diabetic Goto-Kakizaki (GK) rats (N > or = 6/group) were subjected to 35 min ischemia and 120 min of reperfusion. Metformin (50 micromol/l) was added for 15 min at reperfusion, alone or with LY294002 (15 micromol/l), a PI3K inhibitor. Infarct size and Akt phosphorylation were measured. Furthermore, the effect of metformin on mPTP opening in adult cardiomyocytes isolated from both strains was determined.


RESULTS
Metformin reduced infarct size in both Wistar (35 +/- 2.7% metformin vs. 62 +/- 3.0% control: P < 0.05) and GK hearts (43 +/- 4.7% metformin vs. 60 +/- 3.8% control: P < 0.05). This protection was accompanied by a significant increase in Akt phosphorylation. LY294002 abolished the metformin-induced Akt phosphorylation and the infarct-limiting effect of metformin in Wistar (61 +/- 6.7% metformin + LY294002 vs. 35 +/- 2.7% metformin: P < 0.05) and GK rats (56 +/- 5.7% metformin + LY294002 vs. 43 +/- 4.7% metformin: P < 0.05). In addition, metformin significantly inhibited mPTP opening and subsequent rigor contracture in both Wistar and GK cardiomyocytes subjected to oxidative stress, in a LY-sensitive manner.


CONCLUSIONS
We report that metformin given at the time of reperfusion reduces myocardial infarct size in both the non-diabetic and diabetic heart and this protective effect is mediated through PI3K and is associated with Akt phosphorylation. Furthermore, cardioprotection appears to be executed through a PI3K-mediated inhibition of mPTP opening. These findings may explain in part the cardioprotective properties of metformin observed in clinical studies of diabetic patients.
Bhamra
Gurpreet S
GS
The Hatter Cardiovascular Institute, University College London Hospitals, London, WC1E 6HX, UK.
Hausenloy
Derek J
DJ
Davidson
Sean M
SM
Carr
Richard D
RD
Paiva
Marta
M
Wynne
Abigail M
AM
Mocanu
Mihaela M
MM
Yellon
Derek M
DM
D000818:Animals; D002867:Chromones / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D054061:Ischemic Contracture / Q000201:enzymology / Q000517:prevention & control; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009025:Morpholines / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D002867:Chromones; D007004:Hypoglycemic Agents; D008687:Metformin; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one