Role of hypoxia inducible factor-1α in remote limb ischemic preconditioning.

Abstract

Remote ischemic preconditioning (RIPC) has emerged as a feasible and attractive therapeutic procedure for heart protection against ischemia/reperfusion (I/R) injury. However, its molecular mechanisms remain poorly understood. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor that plays a key role in the cellular adaptation to hypoxia and ischemia. This study's aim was to test whether RIPC-induced cardioprotection requires HIF-1α upregulation to be effective. In the first study, wild-type mice and mice heterozygous for HIF1a (gene encoding the HIF-1α protein) were subjected to RIPC immediately before myocardial infarction (MI). RIPC resulted in a robust HIF-1α activation in the limb and acute cardioprotection in wild-type mice. RIPC-induced cardioprotection was preserved in heterozygous mice, despite the low HIF-1α expression in their limbs. In the second study, the role of HIF-1α in RIPC was evaluated using cadmium (Cd), a pharmacological HIF-1α inhibitor. Rats were subjected to MI (MI group) or to RIPC immediately prior to MI (R-MI group). Cd was injected 18 0min before RIPC (Cd-R-MI group). RIPC induced robust HIF-1α activation in rat limbs and significantly reduced infarct size (IS). Despite Cd's inhibition of HIF-1α activation, RIPC-induced cardioprotection was preserved in the Cd-R-MI group. RIPC applied immediately prior to MI increased HIF-1α expression and attenuated IS in rats and wild-type mice. However, RIPC-induced cardioprotection was preserved in partially HIF1a-deficient mice and in rats pretreated with Cd. When considered together, these results suggest that HIF-1α upregulation is unnecessary in acute RIPC.

• Authors: Hussein Kalakech, Sophie Tamareille, Sandrine Pons, Diane Godin-Ribuot, Peter Carmeliet, Alain Furber, Valérie Martin, Alain Berdeaux, Bijan Ghaleh, Fabrice Prunier
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 65 Pg. 98-104 (Dec 2013) ISSN: 1095-8584 [Electronic] England
• PMID: 24140799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Cardiotonic Agents
• Hypoxia-Inducible Factor 1, alpha Subunit
• Cadmium
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Gsk3b protein, rat
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cadmium (pharmacology)
• Cardiotonic Agents (metabolism)
• Enzyme Activation (drug effects)
• Extremities (blood supply, pathology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, deficiency, metabolism)
• Ischemic Preconditioning
• Male
• Mice
• Myocardial Infarction (pathology)
• Myocardium (enzymology, pathology)
• Phosphorylation (drug effects)
• Rats
• Rats, Sprague-Dawley