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  3. Heme: A link between hemorrhage and retinopathy of prematurity progression

Heme: A link between hemorrhage and retinopathy of prematurity progression

  • Redox Biol. 2024 Oct:76:103316. doi: 10.1016/j.redox.2024.103316.
Tamás Gáll 1,  Dávid Pethő 2,  Katalin Erdélyi 3,  Virág Egri 4,  Jázon György Balla 5,  Annamária Nagy 6,  Annamária Nagy 7,  Szilárd Póliska 8,  Magnus Gram 9,  Róbert Gábriel 10,  Péter Nagy 11,  József Balla 6,  György Balla 12
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
  • 2 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.
  • 3 Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest H-1122, Hungary.
  • 4 Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
  • 5 Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
  • 6 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.
  • 7 Department of Ophthalmology, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary.
  • 8 Genomic Medicine and Bioinformatic Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
  • 9 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.
  • 10 Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, H-7624, Hungary; János Szentágothai Research Centre, University of Pécs, Pécs, H-7624, Hungary.
  • 11 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.
  • 12 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. Electronic address: balla@med.unideb.hu.
PMID: 39260060 DOI: 10.1016/j.redox.2024.103316
Abstract

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.

Keywords

Heme; Hypoxia; Mitochondria; Rapamycin; Retinopathy; VEGF.

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