title: HIF-1α in heart: protective mechanisms.
abstract: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that directs many of the cellular responses to hypoxia. In these studies, we have used a mouse model containing a cardiac-specific, oxygen-stabilized, doxycycline (Dox)-off regulated HIF-1α transgene to probe the role of HIF-1α in cardioprotection. Hearts used in these studies were derived from wild-type (WT), noninduced (Non-I), and 2 day (2D) and 6 day (6D) Dox-deprived mice. Whereas HIF-1α protein is undetectable in WT mice, it is present in heart tissue of "noninduced" transgenic mice, presumably because of leakiness of the promoter construct. In mice denied Dox for 2 or 6 days, HIF-1α is overexpressed to a much greater extent than Non-I or WT animals, as expected. WT and HIF-1α-expressing hearts (Non-I, 2D and 6D induced) were subjected to 30 min of ischemia, and functional recovery was measured upon reperfusion. Recovery of preischemic left ventricular developed pressure was 14% for WT, 67% for Non-I hearts, 64% for 2D-induced, and 62% for 6D-induced hearts. 6D-induced HIF hearts have increased preischemic glycogen reserves, higher glycogen synthase protein levels, and significantly higher lactic acid release during ischemia. 6D-induced HIF hearts were also better able to maintain ATP levels during ischemia compared with WT and Non-I hearts. Interestingly, Non-I hearts showed no significant increase in glycogen reserves, glycolytic flux, or greater ATP preservation during ischemia and yet were protected to a similar extent as the 6D-induced hearts. Finally, the mitochondrial membrane potential of isolated adult myocytes was monitored during anoxia or treatments with cyanide and 2-deoxyglucose. HIF-1α expression was shown to protect mitochondrial polarization during both stress treatments. Taken together these data indicate that, while HIF-1α expression in heart does induce increases in compensatory glycolytic capacity, these changes are not necessarily required for cardioprotection, at least in this model of ischemic stress.
authors.affiliation: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University; and.
authors.forename: Joe
authors.initials: J
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Chris
authors.initials: C
authors.lastname: Ardell
authors.forename: Tatyana
authors.initials: T
authors.lastname: Der
authors.forename: Ralph
authors.initials: R
authors.lastname: Shohet
authors.forename: Minghua
authors.initials: M
authors.lastname: Chen
authors.forename: Gary L
authors.initials: GL
authors.lastname: Wright
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002316:Cardiotonic Agents; D006003:Glycogen / Q000378:metabolism*; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology*; D015427:Reperfusion Injury / Q000503:physiopathology*
chemical_list: D002316:Cardiotonic Agents; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D006003:Glycogen; D010100:Oxygen
keywords: cardioprotection; hibernation; mitochondrial and metabolism