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Heme : A link between hemorrhage and retinopathy of prematurity progression

Gáll, Tamás ; Pethő, Dávid ; Erdélyi, Katalin ; Egri, Virág ; Balla, Jázon György ; Nagy, Annamária ; Póliska, Szilárd ; Gram, Magnus LU orcid ; Gábriel, Róbert and Nagy, Péter , et al. (2024) In Redox Biology 76.
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
keywords
Heme, Hypoxia, Mitochondria, Rapamycin, Retinopathy, VEGF
in
Redox Biology
volume
76
article number
103316
publisher
Elsevier
external identifiers
  • pmid:39260060
  • scopus:85203434650
ISSN
2213-2317
DOI
10.1016/j.redox.2024.103316
language
English
LU publication?
yes
id
1c1b66a3-b249-4529-9390-6b07d0682cba
date added to LUP
2024-11-18 15:39:15
date last changed
2025-06-17 08:27:51
@article{1c1b66a3-b249-4529-9390-6b07d0682cba,
  abstract     = {{<p>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.</p>}},
  author       = {{Gáll, Tamás and Pethő, Dávid and Erdélyi, Katalin and Egri, Virág and Balla, Jázon György and Nagy, Annamária and Póliska, Szilárd and Gram, Magnus and Gábriel, Róbert and Nagy, Péter and Balla, József and Balla, György}},
  issn         = {{2213-2317}},
  keywords     = {{Heme; Hypoxia; Mitochondria; Rapamycin; Retinopathy; VEGF}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Redox Biology}},
  title        = {{Heme : A link between hemorrhage and retinopathy of prematurity progression}},
  url          = {{http://dx.doi.org/10.1016/j.redox.2024.103316}},
  doi          = {{10.1016/j.redox.2024.103316}},
  volume       = {{76}},
  year         = {{2024}},
}