Affiliation:
1. From the Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, New York.
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
95 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献