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Desferoxamine and ethyl-3,4-dihydroxybenzoate protect myocardium by activating NOS and generating mitochondrial ROS

Departments of ¹Physiology and ⁴Medicine, University of South Alabama College of Medicine, Mobile, Alabama; ³Division of Cardiology, Pulmonary Disease and Angiology, Department of Medicine, Heinrich-Heine-University, Dusseldorf; and ²Institute of Pathophysiology, University of Essen Medical School, Essen, Germany

Submitted 9 May 2005 ; accepted in final form 2 September 2005

Protection from a prolyl hydroxylase domain-containing enzyme (PHD) inhibitor, desferoxamine (DFO), was recently reported to be dependent on production of reactive oxygen species (ROS). Ischemic preconditioning triggers the protected state by stimulating nitric oxide (NO) production to open mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channels, generating ROS required for protection. We tested whether DFO and a second PHD inhibitor, ethyl-3,4-dihydroxybenzoate (EDHB), might have similar mechanisms. EDHB and DFO increased ROS generation by 50–75% (P < 0.001) in isolated rabbit cardiomyocytes. This increase after EDHB exposure was blocked by N-nitro-L-arginine methyl ester (L-NAME), an NO synthase (NOS) inhibitor; ODQ, a guanylyl cyclase antagonist; and Rp-8-bromoguanosine-3',5'-cyclic monophosphorothioate Rp isomer, a PKG blocker, thus implicating the NO pathway in EDHB's signaling. Glibenclamide, a nonselective K_ATP channel blocker, or 5-hydroxydecanoate, a selective mitoK_ATP channel antagonist, also prevented EDHB's ROS production, as did blockade of mitochondrial electron transport with myxothiazol. NOS is activated by Akt. However, neither wortmannin, an inhibitor of phosphatidylinositol-3-kinase, nor Akt inhibitor blocked EDHB-induced ROS generation, indicating that EDHB initiates signaling downstream of Akt. DFO also increased ROS production, and this effect was blocked by ODQ, 5-hydroxydecanoate, and N-(2-mercaptopropionyl)glycine, an ROS scavenger. DFO increased cardiomyocyte production of nitrite, a metabolite of NO, and this effect was blocked by an inhibitor of NOS. DFO also spared ischemic myocardium in intact hearts. This infarct-sparing effect was blocked by ODQ, L-NAME, and N-(2-mercaptopropionyl)glycine. Hence, DFO and EDHB stimulate NO-dependent activation of PKG to open mitoK_ATP channels and produce ROS, which act as second messengers to trigger entrance into the preconditioned state.

nitric oxide synthase; preconditioning; prolyl hydroxylase inhibitor; reactive oxygen species

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