Uncoupling Proteins 2 and 3 Function in Concert to Augment Tolerance to Cardiac Ischemia

• Published in: The Journal of biological chemistry Vol. 280; no. 39; pp. 33470 - 33476
• Main Authors: McLeod, Christopher J., Aziz, Abdulhameed, Hoyt, Robert F., McCoy, J. Philip, Sack, Michael N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.09.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Hypoxia; Cell Survival; Gene Expression Regulation; Ion Channels; Ischemic Preconditioning, Myocardial; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mitochondria, Heart - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Myocardial Ischemia - metabolism; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - metabolism; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; RNA Interference; Transcription, Genetic; Uncoupling Protein 2; Uncoupling Protein 3
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M505258200

Transient cardiac ischemia activates cell survival signaling, conferring subsequent ischemia tolerance to the heart. This biological phenomenon, termed ischemic preconditioning, results in improved clinical outcome and attenuated infarct size following myocardial infarction. To explore genomic modifications underpinning this ischemia tolerance, we delineated the regulation and function of the cardiac enriched mitochondrial uncoupling proteins 2 and 3 during delayed ischemic preconditioning in the rat. Cardiac transcripts of genes encoding uncoupling proteins 2 and 3 are up-regulated in parallel with infarct size reduction in preconditioned hearts. Mitochondria isolated from preconditioned hearts exhibit an augmented inducible proton leak. In parallel, following anoxia-reoxygenation these mitochondria generate less hydrogen peroxide compared with non-preconditioned mitochondria. Preconditioning in rat cardiac derived myoblasts is abolished following uncoupling protein-2 depletion by RNA-interference. RNAi of uncoupling protein-3 partially attenuates the capacity to precondition these cells. Functional characterization of anoxia and reoxygenation tolerance following uncoupling protein 2 or 3 and combined 2 and 3 RNAi shows the largest reduction in viability follows depletion of both homologues. Uncoupling protein-2 depletion alone significantly attenuates anoxia-reoxygenation tolerance but uncoupling protein-3 depletion does not reduce anoxia tolerance. In parallel combined uncoupling protein depletion and isolated uncoupling protein-2 depletion augments ROS production in viable cardiomyocytes following anoxia-reoxygenation. Concurrent anti-oxidant administration ameliorates the uncoupling protein-depleted anoxia-susceptible phenotype. In conclusion, mitochondrial uncoupling proteins are necessary components of ischemia tolerance and function as components of the cellular antioxidant defense program. In the cytoprotective hierarchy, uncoupling protein-2 appears to play a greater role than uncoupling protein-3 in modulating ischemia/anoxia tolerance in heart-derived cells.