Redox regulation of the mitochondrial K(ATP) channel in cardioprotection

The mitochondrial ATP-sensitive potassium channel (mK(ATP)) is important in the protective mechanism of ischemic preconditioning (IPC). The channel is reportedly sensitive to reactive oxygen and nitrogen species, and the aim of this study was to compare such species in parallel, to build a more comprehensive picture of mK(ATP) regulation. mK(ATP) activity was measured by both osmotic swelling and Tl(+) flux assays, in isolated rat heart mitochondria. An isolated adult rat cardiomyocyte model of ischemia-reperfusion (IR) injury was also used to determine the role of mK(ATP) in cardioprotection by nitroxyl. Key findings were as follows: (i) mK(ATP) was activated by O(2)(center dot-) and H(2)O(2) but not other peroxides. (ii) mK(ATP) was inhibited by NADPH. (iii) mK(ATP) was activated by S-nitrosothiols, nitroxyl, and nitrolinoleate. The latter two species also inhibited mitochondrial complex II. (iv) Nitroxyl protected cardiomyocytes against IR injury in an mK(ATP)-dependent manner. Overall, these results suggest that the mK(ATP) channel is activated by specific reactive oxygen and nitrogen species, and inhibited by NADPH. The redox modulation of mK(ATP) may be an underlying mechanism for its regulation in the context of IPC. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. (C) 2010 Elsevier B.V. All rights reserved.

National Institutes of Health (NIH)[HL-071158]

National Institutes of Health (NIH)

National Institutes of Health (NIH)[GM-087483]

National Institutes of Health (NIH)

John Simon Guggenheim Memorial Foundation

John Simon Guggenheim Memorial Foundation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)

Instituto Nacional de Ciencia e Tecnologia de Processos Redox em Biomedicina (INCT Redoxoma)

Instituto Nacional de Ciencia e Tecnologia de Processos Redox em Biomedicina (INCT Redoxoma)

American Heart Association

American Heart Association[0815770D]