title: Diazoxide prevents reactive oxygen species and mitochondrial damage, leading to anti-hypertrophic effects.
abstract: Pathological cardiac hypertrophy is characterized by wall thickening or chamber enlargement of the heart in response to pressure or volume overload, respectively. This condition will, initially, improve the organ contractile function, but if sustained will render dysfunctional mitochondria and oxidative stress. Mitochondrial ATP-sensitive K+channels (mitoKATP) modulate the redox status of the cell and protect against several cardiac insults. Here, we tested the hypothesis that mitoKATP opening (using diazoxide) will avoid isoproterenol-induced cardiac hypertrophy in vivo by decreasing reactive oxygen species (ROS) production and mitochondrial Ca2+-induced swelling. To induce cardiac hypertrophy, Swiss mice were treated intraperitoneally with isoproterenol (30 mg/kg/day) for 8 days. Diazoxide (5 mg/kg/day) was used to open mitoKATP and 5-hydroxydecanoate (5 mg/kg/day) was administrated as a mitoKATP blocker. Isoproterenol-treated mice had elevated heart weight/tibia length ratios and increased myocyte cross-sectional areas. Additionally, hypertrophic hearts produced higher levels of H2O2and had lower glutathione peroxidase activity. In contrast, mitoKATP opening with diazoxide blocked all isoproterenol effects in a manner reversed by 5-hydroxydecanoate. Isolated mitochondria from Isoproterenol-induced hypertrophic hearts had increased susceptibility to Ca2+-induced swelling secondary to mitochondrial permeability transition pore opening. MitokATP opening was accompanied by lower Ca2+-induced mitochondrial swelling, an effect blocked by 5-hydroxydecanoate. Our results suggest that mitoKATP opening negatively regulates cardiac hypertrophy by avoiding oxidative impairment and mitochondrial damage.
authors.affiliation: Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
authors.forename: Aline M
authors.initials: AM
authors.lastname: Lucas
authors.affiliation: Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
authors.forename: Francisco R
authors.initials: FR
authors.lastname: Caldas
authors.affiliation: Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
authors.forename: Amanda P
authors.initials: AP
authors.lastname: da Silva
authors.affiliation: Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
authors.forename: Maximiano M
authors.initials: MM
authors.lastname: Ventura
authors.affiliation: Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
authors.forename: Iago M
authors.initials: IM
authors.lastname: Leite
authors.affiliation: Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Filgueiras
authors.affiliation: Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
authors.forename: Claúdio G L
authors.initials: CG
authors.lastname: Silva
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Brazil.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
authors.affiliation: Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil. Electronic address: heberty.facundo@ufca.edu.br.
authors.forename: Heberty T
authors.initials: HT
authors.lastname: Facundo
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D003981:Diazoxide / Q000494:pharmacology / Q000627:therapeutic use*; D015640:Ion Channel Gating / Q000187:drug effects; D007545:Isoproterenol; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D007545:Isoproterenol; D003981:Diazoxide; D002118:Calcium
keywords: Calcium; Free radicals; Hypertrophy; Mitochondria; Oxidative stress