title: Cardioprotective HIF-1α-frataxin signaling against ischemia-reperfusion injury.
abstract: Previous studies have demonstrated the protective signaling of hypoxia-inducible factor (HIF)-1 α against ischemia-reperfusion (I/R) injury in the heart. In the present study, we provide further evidence for a cardioprotective mechanism by HIF-1α 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-1α knockout (KO) mice. Furthermore, these HIF-1α KO mice sustained extensive cardiac damage from I/R injury compared with control mice. Similarly, reduction of HIF-1α by RNA inhibition resulted in an attenuation of frataxin expression in response to hypoxia in H9C2 cardiomyocytes. Therefore, we postulated that HIF-1α 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-1α-frataxin signaling promotes a protective mechanism against hypoxic/ischemic stress.
authors.affiliation: Cardio-Metabolic Lab, Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Gayani
authors.initials: G
authors.lastname: Nanayakkara
authors.affiliation: Cardio-Metabolic Lab, Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alasmari
authors.affiliation: Cardio-Metabolic Lab, Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Shravanthi
authors.initials: S
authors.lastname: Mouli
authors.affiliation: Cardio-Metabolic Lab, Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Haitham
authors.initials: H
authors.lastname: Eldoumani
authors.affiliation: School of Kinesiology, Auburn University, Auburn, Alabama; and.
authors.forename: John
authors.initials: J
authors.lastname: Quindry
authors.affiliation: School of Kinesiology, Auburn University, Auburn, Alabama; and.
authors.forename: Graham
authors.initials: G
authors.lastname: McGinnis
authors.affiliation: Cardio-Metabolic Lab, Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Fu
authors.affiliation: Cardio-Metabolic Lab, Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Avery
authors.initials: A
authors.lastname: Berlin
authors.affiliation: School of Kinesiology, Auburn University, Auburn, Alabama; and.
authors.forename: Bridget
authors.initials: B
authors.lastname: Peters
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama.
authors.forename: Juming
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Cardio-Metabolic Lab, Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama; rha0003@auburn.edu.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Amin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000166:cytology / Q000254:growth & development; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D012518:Sarcomeres / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D000096923:Frataxin
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D033862:Iron-Binding Proteins; D000096923:Frataxin; C497443:Hif1a protein, mouse
keywords: frataxin; hypoxia-inducible factor-1α; iron-sulfur; ischemia-reperfusion; mitochondria