Protection of Cardiac Mitochondria by Diazoxide and Protein Kinase C: Implications for Ischemic Preconditioning

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-03, Vol.99 (5), p.3312-3317
• Main Authors: Korge, Paavo, Honda, Henry M., Weiss, James N.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Cell Membrane Permeability - drug effects; Cell Membrane Permeability - physiology; Cellular biology; Cytochromes; Decanoic Acids - pharmacology; Diazoxide - pharmacology; Electrons; Enzyme Activation; Fluorescence; Heart; Hydroxy Acids - pharmacology; Hypoxia; Ice; Ischemia; Ischemic preconditioning; Ischemic Preconditioning, Myocardial; Membrane Potentials - drug effects; Membrane Potentials - physiology; Membranes; Mitochondria; Mitochondria, Heart - drug effects; Mitochondria, Heart - physiology; Oxidation; Oxygen - metabolism; Potassium Channel Blockers; Potassium Channels - agonists; Protective effects; Protein Kinase C - metabolism; Proteins; Rabbits; Swelling
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.052713199

Mitochondrial ATP-sensitive K (mitoKATP) channels play a central role in protecting the heart from injury in ischemic preconditioning. In isolated mitochondria exposed to elevated extramitochondrial Ca, Pi, and anoxia to simulate ischemic conditions, the selective mitoKATPchannel agonist diazoxide (25-50 µM) potently reduced mitochondrial injury by preventing both the mitochondrial permeability transition (MPT) and cytochrome c loss from the intermembrane space. Both effects were blocked completely by the selective mitoKATPantagonist 5-hydroxydecanoate. The protective effect against Ca-induced MPT was most evident under conditions in which the ability of electron transport to support membrane potential (Δψm) was decreased and inner membrane leakiness was increased moderately. Under these conditions, mitoKATPchannel activity strongly regulated Δψm, and diazoxide prevented MPT by inhibiting the driving force for Ca uptake. Phorbol 12-myristate 13-acetate mimicked the protective effects of diazoxide, unless 5-hydroxydecanoate was present, indicating that protein kinase C activation also protects mitochondria by activating mitoKATPchannels. Because Δψmrecovery ultimately is required for heart functional recovery, these results may explain how mitoKATPchannel activation mimics ischemic preconditioning by protecting mitochondria as they pass through a critical vulnerability window during ischemia/reperfusion.