Triggering Mitochondrial Radical Release

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Ischemic preconditioning describes a scenario in which brief intermittent periods of ischemia provide protection against subsequent ischemic injury.1 A number of elements in the signal transduction cascade mediating ischemic preconditioning have been identified. The opening of mitochondrial KATP channels is central for this process, as well as the subsequent release of reactive oxygen species (ROS) from mitochondria, and finally the activation of p38 mitogen–activated protein kinase (p38 MAP kinase). In addition to intermittent ischemia, several agonists, such as acetylcholine, phenylephrine, bradykinin, and opioids have been demonstrated to elicit (pharmacological) preconditioning2 by a similar pathway. In this issue of Hypertension , Kimura et al extend this list of preconditioning agents by including angiotensin II.3 In particular, they demonstrate that angiotensin II leads to the assembly of the NADPH oxidase in the rat myocardium and that inhibition of this assembly process using apocynin blocks angiotensin II–mediated preconditioning. Moreover, the authors observed that inhibition of mitochondrial KATP channels by 5-hydroxydecanoate (5-HD) blocked not only the preconditioning effect of angiotensin II but also prevented the angiotensin II–induced ROS formation from cardiac myocytes. 5-HD had no antioxidative properties and did not block the respiratory burst in leukocytes but prevented ROS formation of isolated mitochondrial preparations. Therefore, the authors conclude that the effects observed in response to angiotensin II in rat myocardium, such as lipid peroxidation, p38 MAP kinase activation, and preconditioning, are mediated by mitochondrial ROS (Figure). Mechanism of angiotensin II–induced …