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Cardiovascular Research 2007 73(3):568-574; doi:10.1016/j.cardiores.2006.11.027
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Copyright © 2006, European Society of Cardiology

The role of poly(ADP-ribose) polymerase (PARP) in the autonomous proliferative response of endothelial cells to hypoxia

Yaser Abdallah*, Dragan Gligorievski, Sascha A. Kasseckert, Lukas Dieterich, Matthias Schäfer, Christoph R. Kuhlmann, Thomas Noll, Heinrich Sauer, H.Michael Piper and Claudia Schäfer

Institute of Physiology, Justus-Liebig-University, D-35392 Giessen, Germany

* Corresponding author. Physiologisches Institut Justus-Liebig-Universität Aulweg 129 D-35392 Giessen Germany. Tel.: +49 6419947223; fax: +49 6419947219. Email address: Yaser.Abdallah{at}physiologie.med.uni-giessen.de

Objective: The autonomous proliferative response of endothelial cells to hypoxia has been shown to be dependent on activation of NAD(P)H oxidase, on the cytosolic Ca2+ load, and, consequently, on nuclear translocation of extracellular signal-regulated kinase (ERK)1/2 during transient hypoxia. The aim of the present study was to investigate whether poly(ADP-ribose) polymerase (PARP) is a downstream signal of NAD(P)H oxidase, mediating cytosolic Ca2+ load and hence nuclear translocation of ERK1/2 and endothelial cell proliferation.

Methods: Porcine aortic endothelial cells were incubated under hypoxic conditions for 40 min. Cytosolic [Ca2+] and reactive oxygen species (ROS) formation were measured in fura-2- and DCF-loaded cells, respectively. PARP activation was detected by immunocytochemistry, and endothelial cell proliferation was determined 24 h after 60 min of transient hypoxia.

Results: Inhibition of NAD(P)H oxidase with antisense oligonucleotide against the p22phox subunit, MEK/ERK signalling with UO 126 (30 µM), or PARP with PJ 34 (10 µM) leads to a marked reduction in hypoxia-induced cytosolic Ca2+ load and activation of PARP. Hypoxia-induced translocation of ERK1/2 and endothelial cell proliferation were also prevented when NAD(P)H oxidase or PARP were inhibited; however, hypoxic ROS formation was not affected in the presence of PARP inhibitor.

Conclusion: PARP represents a downstream effector of NADP(H) oxidase and acts as a necessary intermediate step for the hypoxic proliferative response of endothelial cells.

KEYWORDS PARP; Hypoxia; Endothelial cell; Proloferation; Calcium; ROS

* Hiroshi Watanabe (Hamamatsu University, Japan)

Time for primary review 34 days


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