| First Author | Wu J | Year | 2013 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 305 |
| Issue | 6 | Pages | H821-8 |
| PubMed ID | 23873797 | Mgi Jnum | J:202229 |
| Mgi Id | MGI:5517719 | Doi | 10.1152/ajpheart.00140.2013 |
| Citation | Wu J, et al. (2013) HIF-1alpha in heart: protective mechanisms. Am J Physiol Heart Circ Physiol 305(6):H821-8 |
| abstractText | Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha transgene to probe the role of HIF-1alpha 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-1alpha 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-1alpha is overexpressed to a much greater extent than Non-I or WT animals, as expected. WT and HIF-1alpha-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-1alpha expression was shown to protect mitochondrial polarization during both stress treatments. Taken together these data indicate that, while HIF-1alpha 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. |
