title: The beneficial effects of AMP kinase activation against oxidative stress are associated with prevention of PPARα-cyclophilin D interaction in cardiomyocytes.
abstract: AMP kinase (AMPK) plays an important role in the regulation of energy metabolism in cardiac cells. Furthermore, activation of AMPK protects the heart from myocardial infarction and heart failure. The present study examines whether or not AMPK affects the peroxisome proliferator-activated receptor-α (PPARα)/mitochondria pathway in response to acute oxidative stress in cultured cardiomyocytes. Cultured H9c2 rat embryonic cardioblasts were exposed to H2O2-induced acute oxidative stress in the presence or absence of metformin, compound C (AMPK inhibitor), GW6471 (PPARα inhibitor), or A-769662 (AMPK activator). Results showed that AMPK activation by metformin reverted oxidative stress-induced inactivation of AMPK and prevented oxidative stress-induced cell death. In addition, metformin attenuated reactive oxygen species generation and depolarization of the inner mitochondrial membrane. The antioxidative effects of metformin were associated with the prevention of mitochondrial DNA damage in cardiomyocytes. Coimmunoprecipitation studies revealed that metformin abolished oxidative stress-induced physical interactions between PPARα and cyclophilin D (CypD), and the abolishment of these interactions was associated with inhibition of permeability transition pore formation. The beneficial effects of metformin were not due to acetylation or phosphorylation of PPARα in response to oxidative stress. In conclusion, this study demonstrates that the protective effects of metformin-induced AMPK activation against oxidative stress converge on mitochondria and are mediated, at least in part, through the dissociation of PPARα-CypD interactions, independent of phosphorylation and acetylation of PPARα and CypD.
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico; and.
authors.forename: Giselle
authors.initials: G
authors.lastname: Barreto-Torres
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico; and.
authors.forename: Jessica Soto
authors.initials: JS
authors.lastname: Hernandez
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico; and.
authors.forename: Sehwan
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico; and.
authors.forename: Adlín R
authors.initials: AR
authors.lastname: Rodríguez-Muñoz
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico; and.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Torres-Ramos
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Alexei G
authors.initials: AG
authors.lastname: Basnakian
authors.affiliation: Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico; and sabzali.javadov@upr.edu.
authors.forename: Sabzali
authors.initials: S
authors.lastname: Javadov
mesh_terms: D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001713:Biphenyl Compounds; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D021983:Cyclophilins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology; D000097322:Peptidyl-Prolyl Isomerase D
chemical_list: D000263:Adenylate Kinase; D000975:Antioxidants; D001713:Biphenyl Compounds; D021983:Cyclophilins; D020536:Enzyme Activators; D008687:Metformin; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016877:Oxidants; D047493:PPAR alpha; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D017382:Reactive Oxygen Species; D013876:Thiophenes; C581109:Ppid protein, rat; D000097322:Peptidyl-Prolyl Isomerase D; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AMPK; H9c2 cardiomyocytes; PPARα; metformin; mitochondria; oxidative stress