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on January 31, 2008

Arteriosclerosis, Thrombosis, and Vascular Biology. 2008
Published online before print January 31, 2008, doi: 10.1161/ATVBAHA.107.156406
A more recent version of this article appeared on April 1, 2008
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*Substance via MeSH

Submitted on July 5, 2007
Accepted on January 15, 2008

PARP-1 Inhibition Prevents Oxidative and Nitrosative Stress–Induced Endothelial Cell Death via Transactivation of the VEGF Receptor 2

Marlene T. Mathews and Bradford C. Berk *

From the Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, New York.

* To whom correspondence should be addressed. E-mail: Bradford_Berk{at}urmc.rochester.edu.

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 (H2O2) and peroxynitrite (ONOO-). Both depleted HUVECs of NAD+ and ATP, processes that were limited by the PARP-1 inhibitor, PJ34. ONOO- and H2O2-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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