Heme: A link between hemorrhage and retinopathy of prematurity progression
Tamás Gáll,
Dávid Pethő,
Katalin Erdélyi,
Virág Egri,
Jázon György Balla,
Annamária Nagy,
Annamária Nagy,
Szilárd Póliska,
Magnus Gram,
Róbert Gábriel,
Péter Nagy,
József Balla,
György Balla
Affiliations
Tamás Gáll
Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
Dávid Pethő
Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary; HUN-REN–UD Vascular Biology and Myocardium Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, Debrecen, H-4032, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
Katalin Erdélyi
Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest H-1122, Hungary
Virág Egri
Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
Jázon György Balla
Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
Annamária Nagy
Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary; HUN-REN–UD Vascular Biology and Myocardium Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, Debrecen, H-4032, Hungary
Annamária Nagy
Department of Ophthalmology, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
Szilárd Póliska
Genomic Medicine and Bioinformatic Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary
Magnus Gram
Pediatrics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Neonatology, Skåne University Hospital, Lund, Sweden; Biofilms – Research Center for Biointerfaces, Department of Biomedical Science, Faculty of Health and Society, Malmö University, Malmö, Sweden
Róbert Gábriel
Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, H-7624, Hungary; János Szentágothai Research Centre, University of Pécs, Pécs, H-7624, Hungary
Péter Nagy
Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest H-1122, Hungary; Chemistry Institute, University of Debrecen, Debrecen, H-4032, Hungary; Department of Anatomy and Histology, HUN-REN-UVMB Laboratory of Redox Biology, University of Veterinary Medicine; Budapest, Hungary
József Balla
Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary; HUN-REN–UD Vascular Biology and Myocardium Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, Debrecen, H-4032, Hungary
György Balla
Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary; Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary; Corresponding author. Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
Neovascularization is implicated in the pathology of retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD), which are the leading causes of blindness worldwide. In our work, we analyzed how heme released during hemorrhage affects hypoxic response and neovascularization. Our retrospective clinical analysis demonstrated, that hemorrhage was associated with more severe retinal neovascularization in ROP patients. Our heme-stimulated human retinal pigment epithelial (ARPE-19) cell studies demonstrated increased expression of positive regulators of angiogenesis, including vascular endothelial growth factor-A (VEGFA), a key player of ROP, DR and AMD, and highlighted the activation of the PI3K/AKT/mTOR/VEGFA pathway involved in angiogenesis in response to heme. Furthermore, heme decreased oxidative phosphorylation in the mitochondria, augmented glycolysis, facilitated HIF-1α nuclear translocation, and increased VEGFA/GLUT1/PDK1 expression suggesting HIF-1α-driven hypoxic response in ARPE-19 cells without effecting the metabolism of reactive oxygen species. Inhibitors of HIF-1α, PI3K and suppression of mTOR pathway by clinically promising drug, rapamycin, mitigated heme-provoked cellular response. Our data proved that oxidatively modified forms of hemoglobin can be sources of heme to induce VEGFA during retinal hemorrhage. We propose that hemorrhage is involved in the pathology of ROP, DR, and AMD.
