Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury.
BACKGROUND
Preconditioning phenomena provide evidence for adaptive responses to ischemia that have important implications for treatment/prevention of myocardial infarction. Hypoxia-inducible factor 1 (HIF-1) mediates adaptive transcriptional responses to hypoxia/ischemia.


RESULTS
Exposure of wild-type mice to intermittent hypoxia resulted in protection of isolated hearts against ischemia-reperfusion injury 24 hours later. Cardiac protection induced by intermittent hypoxia was lost in Hif1a+/- mice heterozygous for a knockout allele at the locus encoding HIF-1alpha. Erythropoietin (EPO) mRNA expression was induced in kidneys of wild-type mice subjected to intermittent hypoxia, resulting in increased plasma EPO levels. EPO mRNA expression was not induced in Hif1a+/- mice. EPO administration to rats increased functional recovery and decreased apoptosis in isolated hearts subjected to ischemia-reperfusion 24 hours later.


CONCLUSIONS
Hearts isolated from rodents subjected to intermittent hypoxia or EPO administration are protected against postischemic injury. Cardiac protection induced by intermittent hypoxia is critically dependent on Hif1a gene dosage. Our data suggest that additional studies to evaluate therapeutic applications of EPO administration are warranted.
Cai
Zheqing
Z
McKusick-Nathans Institute of Genetic Medicine, Baltimore, MD, USA.
Manalo
Dominador J
DJ
Wei
Guo
G
Rodriguez
E Rene
ER
Fox-Talbot
Karen
K
Lu
Huasheng
H
Zweier
Jay L
JL
Semenza
Gregg L
GL
D000818:Animals; D004921:Erythropoietin / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D015870:Gene Expression; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006579:Heterozygote; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000517:prevention & control*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D014157:Transcription Factors; D004921:Erythropoietin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat