The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
PARP-1 Inhibition Prevents Oxidative and Nitrosative Stress–Induced Endothelial Cell Death via Transactivation of the VEGF Receptor 2
Abstract
Objective— PARP-1, a DNA base repair enzyme, is activated by DNA breaks induced by oxidative (ROS) and nitrosative (RNS) stress. By consuming NAD + , PARP-1 activation can lead to ATP depletion and cell death. Studies suggest that inhibiting PARP-1 activity can attenuate pathologies associated with vascular smooth muscle and endothelial dysfunction. PARP-1 inhibition can also activate the prosurvival serine/threonine kinase, Akt. Vascular endothelial growth factor (VEGF) regulates endothelial cell survival via Akt activation downstream of VEGF receptor 2 (VEGFR2) activation. Here we investigated the hypothesis that PARP-1 inhibition protects human umbilical vein endothelial cells (HUVECs) from ROS- and RNS-induced cell death by limiting NAD + depletion and by activating a prosurvival signaling pathway via VEGFR2 phosphorylation. Methods and Results— We activated PARP-1 in HUVECs by treatment with hydrogen peroxide (H 2 O 2 ) and peroxynitrite (ONOO − ). Both depleted HUVECs of NAD + and ATP, processes that were limited by the PARP-1 inhibitor, PJ34. ONOO − and H 2 O 2 -induced cell death and apoptosis were attenuated in cells treated with PJ34 or PARP-1 siRNA. PARP-1 inhibition increased Akt, BAD, and VEGFR2 phosphorylation in HUVECs and in PJ34-treated rabbit aortas. The VEGFR2-specific tyrosine kinase inhibitor SU1498 decreased PARP-1 inhibition-mediated phosphorylation of VEGFR2 and Akt, and also reversed survival effects of PJ34. Finally, PARP-1 inhibition protected cells from death induced by serum starvation, evidence for a role in cell survival independent of energy protection. Conclusions— PARP-1 inhibition prevents ROS- and RNS-induced HUVEC death by maintaining cellular energy in the form of NAD + and ATP, and also by activating a survival pathway via VEGFR2, Akt, and BAD phosphorylation.
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Metadata
- Authors
- Mathews, M. T., & Berk, B. C.
- Affiliations
- University of Rochester Medicine (US)
- ORCID
- Berk, Bradford C.
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2008-04
- Volume
- 28
- Issue
- 4
- Pages
- 711-717
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2080180491
- Cited by
- 120
- References
- 30
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 5 · 2021: 8 · 2020: 9 · 2019: 3 · 2018: 4 · 2017: 10 · 2016: 6 · 2015: 6 · 2014: 4 · 2013: 13 · 2012: 7
- FWCI
- 3.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- PARP1 inhibition, oxidative stress, nitrosative stress, endothelial cell death, VEGF receptor 2, Akt signaling, Bad phosphorylation, NAD+ depletion, ATP depletion, hydrogen peroxide, peroxynitrite, PJ34, endothelial cell survival, apoptosis, human umbilical vein endothelial cells
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Poly (ADP-Ribose) Polymerase-1, Adenosine Triphosphate, Cells, Cultured, Cinnamates, Enzyme Inhibitors, Humans, NAD, Oxidation-Reduction, Phenanthrenes, Poly(ADP-ribose) Polymerases, Transcriptional Activation, Nitrosation, Cell Death, Apoptosis, Oxidative Stress, Reactive Nitrogen Species, RNA, Small Interfering, Vascular Endothelial Growth Factor Receptor-2, Endothelial Cells
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