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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-11339

von Lukowicz, T; Hassa, P O; Lohmann, C; Borén, J; Braunersreuther, V; Mach, F; Odermatt, B; Gersbach, M; Camici, G G; Stähli, B E; Tanner, F C; Hottiger, M O; Lüscher, T F; Matter, C M (2008). PARP1 is required for adhesion molecule expression in atherogenesis. Cardiovascular Research, 78(1):158-166.

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Abstract

AIMS: Atherosclerosis is the leading cause of death in Western societies and a chronic inflammatory disease. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme, which plays a role in acute inflammatory diseases. METHODS AND RESULTS: In order to test the role of PARP in atherogenesis, we applied chronic pharmacological PARP inhibition or genetic PARP1 deletion in atherosclerosis-prone apolipoprotein E-deficient mice and measured plaque formation, adhesion molecules, and features of plaque vulnerability. After 12 weeks of high-cholesterol diet, plaque formation in male apolipoprotein E-deficient mice was decreased by chronic inhibition of enzymatic PARP activity or genetic deletion of PARP1 by 46 or 51%, respectively (P < 0.05, n >or= 9). PARP inhibition or PARP1 deletion reduced PARP activity and diminished expression of inducible nitric oxide synthase, vascular cell adhesion molecule-1, and P- and E-selectin. Furthermore, chronic PARP inhibition reduced plaque macrophage (CD68) and T-cell infiltration (CD3), increased fibrous cap thickness, and decreased necrotic core size and cell death (P < 0.05, n >or= 6). CONCLUSION: Our data provide pharmacological and genetic evidence that endogenous PARP1 is required for atherogenesis in vivo by increasing adhesion molecules with endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising therapeutic target in atherosclerosis.

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29 citations in Web of Science®
31 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Biochemistry and Molecular Biology
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2008
Deposited On:23 Jan 2009 17:02
Last Modified:27 Nov 2013 18:40
Publisher:Oxford University Press
ISSN:0008-6363
Funders:EU Grant, Bundesamt für Bildung und Wissenschaft, Swiss National Science Foundation, URPP "Integrative Human Physiology", Novartis Research Foundation, Kanton of Zurich
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:10.1093/cvr/cvm110
PubMed ID:18093987

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