title: Mitochondrial ATP-sensitive potassium channel opening inhibits isoproterenol-induced cardiac hypertrophy by preventing oxidative damage.
abstract: Cardiac hypertrophy is a chronic complex disease that occurs in response to hemodynamic load and is accompanied by oxidative stress and mitochondrial dysfunction. Mitochondrial ATP-sensitive K channels (mitoKATPs) have previously been shown to prevent oxidative cardiac damage under conditions of ischemia/reperfusion. However, the effect of these channels on cardiac hypertrophy has not been tested to date. In this study, we show that treatment of Swiss mice with isoproterenol (30 mg·kg·d) induces cardiac hypertrophy while significantly decreasing the levels of reduced protein thiols, glutathione, catalase, and superoxide dismutase activity, indicative of a condition of oxidative imbalance. Treatment with diazoxide (a mitoKATP opener, 5 mg·kg·d) normalized the levels of protein thiols and reduced glutathione, rescued superoxide dismutase activity, and significantly prevented cardiac hypertrophy. The protective effects of diazoxide were mitigated by the mitoKATP blockers 5-hydroxydecanoate (5 mg·kg·d) and glibenclamide (3 mg·kg·d), demonstrating that they were related to activation of the channel. Taken together, our results establish that mitoKATP activation promotes very robust prevention of cardiac hypertrophy and associated oxidative imbalance and suggest that these channels can be important drug targets for the pharmacological control of cardiac hypertrophy.
authors: *Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, Brazil; and †Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors: Francisco Rodrigo
authors: FR
authors: Lemos Caldas
authors: Iago Mateus
authors: IM
authors: Rocha Leite
authors: Ana Beatriz
authors: AB
authors: Tavarez Filgueiras
authors: Isaias Lima
authors: IL
authors: de Figueiredo Júnior
authors: Tereza Amália
authors: TA
authors: Gomes Marques de Sousa
authors: Pamela Reis
authors: PR
authors: Martins
authors: Alicia Juliana
authors: AJ
authors: Kowaltowski
authors: Heberty di Tarso
authors: Hd
authors: Fernandes Facundo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D004195:Disease Models, Animal; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D015221:Potassium Channels / Q000378:metabolism*; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002316:Cardiotonic Agents; D015221:Potassium Channels; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D003981:Diazoxide