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.
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.
© 2013.