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- Title
The role of poly(ADP-ribose) polymerase (PARP) in the autonomous proliferative response of endothelial cells to hypoxia
- Authors
Abdallah, Yaser; Gligorievski, Dragan; Kasseckert, Sascha A.; Dieterich, Lukas; Schäfer, Matthias; Kuhlmann, Christoph R.; Noll, Thomas; Sauer, Heinrich; Piper, H.Michael; Schäfer, Claudia
- Abstract
Abstract: 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.
- Subjects
HYPOXEMIA; ENDOTHELIUM; OXIDASES; NAD(P)H dehydrogenases; POLY(ADP-ribose) polymerase; CELL proliferation; IMMUNOCYTOCHEMISTRY
- Publication
Cardiovascular Research, 2007, Vol 73, Issue 3, p568
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1016/j.cardiores.2006.11.027