| First Author | Nanayakkara G | Year | 2015 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 309 |
| Issue | 5 | Pages | H867-79 |
| PubMed ID | 26071548 | Mgi Jnum | J:226357 |
| Mgi Id | MGI:5697126 | Doi | 10.1152/ajpheart.00875.2014 |
| Citation | Nanayakkara G, et al. (2015) Cardioprotective HIF-1alpha-frataxin signaling against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 309(5):H867-79 |
| abstractText | Previous studies have demonstrated the protective signaling of hypoxia-inducible factor (HIF)-1 alpha against ischemia-reperfusion (I/R) injury in the heart. In the present study, we provide further evidence for a cardioprotective mechanism by HIF-1alpha against I/R injury exerted via the mitochondrial protein frataxin, which regulates mitochondrial Fe-S cluster formation. Disruption of frataxin has been found to induce mitochondrial iron overload and subsequent ROS production. We observed that frataxin expression was elevated in mice hearts subjected to I/R injury, and this response was blunted in cardiomyocyte-specific HIF-1alpha knockout (KO) mice. Furthermore, these HIF-1alpha KO mice sustained extensive cardiac damage from I/R injury compared with control mice. Similarly, reduction of HIF-1alpha by RNA inhibition resulted in an attenuation of frataxin expression in response to hypoxia in H9C2 cardiomyocytes. Therefore, we postulated that HIF-1alpha transcriptionally regulates frataxin expression in response to hypoxia and offers a cardioprotective mechanism against ischemic injury. Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. Our data also suggest that increased frataxin mitigated mitochondrial iron overload and subsequent ROS production, thus preserving mitochondrial membrane integrity and viability of cardiomyocytes. We postulate that frataxin may exert its beneficial effects by acting as an iron storage protein under hypoxia and subsequently facilitates the maintenance of mitochondrial membrane potential and promotes cell survival. The findings from our study revealed that HIF-1alpha-frataxin signaling promotes a protective mechanism against hypoxic/ischemic stress. |
