Fig. 1

Proposed cardioprotective mechanisms of metformin. It is suggested that metformin confers cardioprotection by inhibiting mitochondrial complex I and inhibiting AMP deaminase, which both increase cytosolic AMP:ATP ratio. This activates AMPK causing the phosphorylation of eNOS, an integral part of the RISK pathway. Furthermore, increased AMP:ATP facilitates the extracellular diffusion of adenosine and its subsequent activation of the RISK pathway via a G protein-coupled receptor. Metformin may also activate PI3K directly. The RISK pathway inhibits MPTP opening which mitigates the detrimental effects of calcium influx and ROS generation at reperfusion. Ado adenosine, AMP adenosine monophosphate, AMPK adenosine monophosphate-activated protein kinase, ATP adenosine triphosphate, eNOS endothelial nitric oxide synthase, ENT equilibrative nucleoside transporter; Erk, extracellular signal-regulated kinases, GPCR G protein-coupled receptor, IMP inosine monophosphate, MEK1/2 mitogen-activated protein kinase, mK _ATP mitochondrial ATP-sensitive potassium channel, mPKC mitochondrial protein kinase C, MPTP mitochondrial permeability transition pore, NADH nicotinamide adenine dinucleotide, NO nitric oxide, OCT1 organic cation transporter 1, PI3K phosphoinositide 3 kinase, RISK reperfusion injury salvage kinase, ROS reactive oxygen species.