PARP inhibitor protects against chronic hypoxia/ reoxygenation-induced retinal injury by regulation of MAPKs, HIF1α, Nrf2, and NFjB

Krisztina Kovacs, Alexandra Vaczy, Katalin Fekete, Kovari Petra Kovari, Tamas Atlasz, D. Reglodi, R. Gábriel, F. Gallyas, B. Sümegi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

PURPOSE. In the eye, chronic hypoxia/reoxygenation (H/R) contributes to the development of a number of ocular disorders. H/R induces the production of reactive oxygen species (ROS), leading to poly(ADP-ribose) polymerase-1 (PARP1) activation that promotes inflammation, cell death, and disease progression. Here, we analyzed the protective effects of the PARP1 inhibitor olaparib in H/R-induced retina injury and investigated the signaling mechanisms involved. METHODS. A rat retinal H/R model was used to detect histologic and biochemical changes in the retina. RESULTS. H/R induced reductions in the thickness of most retinal layers, which were prevented by olaparib. Furthermore, H/R caused increased levels of Akt and glycogen synthase kinase-3b phosphorylation, which were further increased by olaparib, contributing to retina protection. By contrast, H/R-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinases (MAPK) phosphorylation and activation were reduced by olaparib, via mitogen-activated protein kinase phosphatase 1 (MKP-1) expression. In addition, H/R-induced hypoxia-inducible factor 1α (HIF1α) levels were decreased by olaparib, which possibly contributed to reduced VEGF expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was slightly increased by H/R and was further activated by olaparib. Nuclear factor-jB (NFjB) was also activated by H/R through phosphorylation (Ser536) and acetylation (Lys310) of the p65 subunit, although this was significantly reduced by olaparib. CONCLUSIONS. Olaparib reduced H/R-induced degenerative changes in retinal morphology. The protective mechanisms of olaparib most probably involved Nrf2 activation and ROS reduction, as well as normalization of HIF1α and related VEGF expression. In addition, olaparib reduced inflammation by NFjB dephosphorylation/inactivation, possibly via the PARP1 inhibition-MKP-1 activation-p38 MAPK inhibition pathway. PARP inhibitors represent potential therapeutics in H/R-induced retinal disease.

Original languageEnglish
Pages (from-to)1478-1490
Number of pages13
JournalInvestigative Ophthalmology and Visual Science
Volume60
Issue number5
DOIs
Publication statusPublished - Apr 1 2019

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Hypoxia-Inducible Factor 1
Wounds and Injuries
Mitogen-Activated Protein Kinase Phosphatases
Dual Specificity Phosphatase 1
Retina
Phosphorylation
p38 Mitogen-Activated Protein Kinases
Vascular Endothelial Growth Factor A
Hypoxia
Poly(ADP-ribose) Polymerase Inhibitors
Reactive Oxygen Species
olaparib
Inflammation
Glycogen Synthase Kinases
Retinal Diseases
JNK Mitogen-Activated Protein Kinases
Acetylation
Disease Progression
Cell Death

Keywords

  • MAPKs
  • NFkB
  • PARP
  • Retinal ischemia
  • Transcription factors

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

PARP inhibitor protects against chronic hypoxia/ reoxygenation-induced retinal injury by regulation of MAPKs, HIF1α, Nrf2, and NFjB. / Kovacs, Krisztina; Vaczy, Alexandra; Fekete, Katalin; Petra Kovari, Kovari; Atlasz, Tamas; Reglodi, D.; Gábriel, R.; Gallyas, F.; Sümegi, B.

In: Investigative Ophthalmology and Visual Science, Vol. 60, No. 5, 01.04.2019, p. 1478-1490.

Research output: Contribution to journalArticle

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AU - Vaczy, Alexandra

AU - Fekete, Katalin

AU - Petra Kovari, Kovari

AU - Atlasz, Tamas

AU - Reglodi, D.

AU - Gábriel, R.

AU - Gallyas, F.

AU - Sümegi, B.

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N2 - PURPOSE. In the eye, chronic hypoxia/reoxygenation (H/R) contributes to the development of a number of ocular disorders. H/R induces the production of reactive oxygen species (ROS), leading to poly(ADP-ribose) polymerase-1 (PARP1) activation that promotes inflammation, cell death, and disease progression. Here, we analyzed the protective effects of the PARP1 inhibitor olaparib in H/R-induced retina injury and investigated the signaling mechanisms involved. METHODS. A rat retinal H/R model was used to detect histologic and biochemical changes in the retina. RESULTS. H/R induced reductions in the thickness of most retinal layers, which were prevented by olaparib. Furthermore, H/R caused increased levels of Akt and glycogen synthase kinase-3b phosphorylation, which were further increased by olaparib, contributing to retina protection. By contrast, H/R-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinases (MAPK) phosphorylation and activation were reduced by olaparib, via mitogen-activated protein kinase phosphatase 1 (MKP-1) expression. In addition, H/R-induced hypoxia-inducible factor 1α (HIF1α) levels were decreased by olaparib, which possibly contributed to reduced VEGF expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was slightly increased by H/R and was further activated by olaparib. Nuclear factor-jB (NFjB) was also activated by H/R through phosphorylation (Ser536) and acetylation (Lys310) of the p65 subunit, although this was significantly reduced by olaparib. CONCLUSIONS. Olaparib reduced H/R-induced degenerative changes in retinal morphology. The protective mechanisms of olaparib most probably involved Nrf2 activation and ROS reduction, as well as normalization of HIF1α and related VEGF expression. In addition, olaparib reduced inflammation by NFjB dephosphorylation/inactivation, possibly via the PARP1 inhibition-MKP-1 activation-p38 MAPK inhibition pathway. PARP inhibitors represent potential therapeutics in H/R-induced retinal disease.

AB - PURPOSE. In the eye, chronic hypoxia/reoxygenation (H/R) contributes to the development of a number of ocular disorders. H/R induces the production of reactive oxygen species (ROS), leading to poly(ADP-ribose) polymerase-1 (PARP1) activation that promotes inflammation, cell death, and disease progression. Here, we analyzed the protective effects of the PARP1 inhibitor olaparib in H/R-induced retina injury and investigated the signaling mechanisms involved. METHODS. A rat retinal H/R model was used to detect histologic and biochemical changes in the retina. RESULTS. H/R induced reductions in the thickness of most retinal layers, which were prevented by olaparib. Furthermore, H/R caused increased levels of Akt and glycogen synthase kinase-3b phosphorylation, which were further increased by olaparib, contributing to retina protection. By contrast, H/R-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinases (MAPK) phosphorylation and activation were reduced by olaparib, via mitogen-activated protein kinase phosphatase 1 (MKP-1) expression. In addition, H/R-induced hypoxia-inducible factor 1α (HIF1α) levels were decreased by olaparib, which possibly contributed to reduced VEGF expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was slightly increased by H/R and was further activated by olaparib. Nuclear factor-jB (NFjB) was also activated by H/R through phosphorylation (Ser536) and acetylation (Lys310) of the p65 subunit, although this was significantly reduced by olaparib. CONCLUSIONS. Olaparib reduced H/R-induced degenerative changes in retinal morphology. The protective mechanisms of olaparib most probably involved Nrf2 activation and ROS reduction, as well as normalization of HIF1α and related VEGF expression. In addition, olaparib reduced inflammation by NFjB dephosphorylation/inactivation, possibly via the PARP1 inhibition-MKP-1 activation-p38 MAPK inhibition pathway. PARP inhibitors represent potential therapeutics in H/R-induced retinal disease.

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KW - Retinal ischemia

KW - Transcription factors

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