title: The role of PPARα in metformin-induced attenuation of mitochondrial dysfunction in acute cardiac ischemia/reperfusion in rats.
abstract: Metformin, an anti-diabetic drug, exerts cardioprotection against ischemia-reperfusion (IR) through the activation of AMPK. However, the molecular mechanisms underlying these beneficial effects remain elusive. In this study, we examined the role of PPARα in mediating cardioprotective effects of metformin on mitochondria. Hearts of male Sprague-Dawley rats perfused by Langendorff were subjected to IR in the presence or absence of metformin and the PPARβ inhibitor, GW6471. IR reduced cardiac function and compromised the structural integrity of cardiac cells evidenced by increased LDH release from the hearts. In addition, IR induced mitochondrial dysfunction as evidenced by reduced respiration and increased mitochondrial permeability transition pore (PTP) opening. However, metformin-treated hearts demonstrated improved post-ischemic recovery of cardiac function and reduced cell death that were associated with increased state 3 respiration at complexes I and II (by 27% and 32%, respectively, both p < 0.05) and decreased PTP opening (by 27%, p < 0.05) compared to untreated hearts. The protective effects of metformin on cardiac function and mitochondria were blocked by GW6471. Thus, our results demonstrate that inhibition of PPARα attenuates the beneficial effects of metformin on mitochondria in acute IR.
authors: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936, USA.
authors: Giselle
authors: G
authors: Barreto-Torres
authors: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936, USA.
authors: Rebecca
authors: R
authors: Parodi-Rullán
authors: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR 00936, USA.
authors: Sabzali
authors: S
authors: Javadov
mesh_terms: D000818:Animals; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C449302:GW 6471; D007004:Hypoglycemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D014443:Tyrosine; D008687:Metformin; D007770:L-Lactate Dehydrogenase; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I