AMPK‐induced inhibition of mitochondrial dysfunction is mediated through PPAR‐alpha in acute cardiac ischemia/reperfusion

Abstract

AMP-activated protein kinase (AMPK) activation has been demonstrated to exert cardioprotective effects against ischemia-reperfusion (IR), however the detailed cellular mechanisms mediating these effects remain elusive. In this study, we examined whether cardioprotective effects of AMPK on mitochondria is mediated through peroxisome proliferator-activated receptor α (PPARα). Langendorff-perfused rat hearts subjected to IR were divided into four groups: 1) IR, 2) IR+2mM metformin (Met, AMPK activator), 3) IR+0.30μM GW6471 (GW, PPARα inhibitor) and IR+Met+GW. IR-induced cardiac dysfunction was associated with reduced mitochondrial respiration and increased mitochondrial permeability transition pore (mPTP) opening, as determined by monitoring the decrease of light scattering with Ca2+. Met-treated hearts demonstrated improved post-ischemic recovery of cardiac function (left ventricular developed pressure in IR: 22% vs Met: 36% of pre-ischemia; P<0.05), increased state 3 respiratory rate at complexes I and II (by 27% and 32%, respectively, compared to IR; P<0.05) and decreased mPTP opening (IR: 97% vs Met: 70% of max swelling; P<0.05). The protective effect of Met was blocked by GW. These results demonstrate that the beneficial effect of AMPK activation on mitochondria is mediated through PPARα in acute IR. Supported by the American Physiological Society.