title: 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.affiliation: LUNAM Université, Angers, France; Laboratoire Cardioprotection, Remodelage et Thrombose, Angers, France.
authors.forename: Hussein
authors.initials: H
authors.lastname: Kalakech
authors.forename: Sophie
authors.initials: S
authors.lastname: Tamareille
authors.forename: Sandrine
authors.initials: S
authors.lastname: Pons
authors.forename: Diane
authors.initials: D
authors.lastname: Godin-Ribuot
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Alain
authors.initials: A
authors.lastname: Furber
authors.forename: Valérie
authors.initials: V
authors.lastname: Martin
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.forename: Bijan
authors.initials: B
authors.lastname: Ghaleh
authors.forename: Fabrice
authors.initials: F
authors.lastname: Prunier
mesh_terms: D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005121:Extremities / Q000098:blood supply* / Q000473:pathology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D019194:Ischemic Preconditioning; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002316:Cardiotonic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002104:Cadmium; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: AAR; Cd; DNA; GAPDH; GSK-3β; HIF-1α; HIF1a; Hypoxia inducible factor-1α; I/R; IPC; IS; Ischemia/reperfusion injury; MI; NF-κB; P-GSK-3β; PCR; PTEN; RIPC; Remote ischemic preconditioning; SEM; TTC; VEGF; area at risk; cadmium; deoxyribonucleic acid; gene encoding the HIF-1α protein; glyceraldehyde 3-phosphate dehydrogenase; hypoxia inducible factor-1α; infarct size; ischemia/reperfusion; local ischemic preconditioning; myocardial infarction; nuclear factor-kappa B; phosphatase and tensin homolog; phospho-Glycogen Synthase Kinase-3β; polymerase chain reaction; remote ischemic preconditioning; siRNA; small interfering RNA; standard error of the mean; total GSK-3β; triphenyltetrazolium chloride; vascular endothelial growth factor