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PARP1 is required for adhesion molecule expression in atherogenesis

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.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
05 Vetsuisse Faculty > Veterinärwissenschaftliches Institut > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease

04 Faculty of Medicine > Zurich Center for Integrative Human Physiology (ZIHP)
National licences > 142-005
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Physiology
Health Sciences > Cardiology and Cardiovascular Medicine
Health Sciences > Physiology (medical)
Language:English
Date:2008
Deposited On:23 Jan 2009 17:02
Last Modified:04 Jul 2025 03:41
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
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/cvr/cvm110
PubMed ID:18093987
Project Information:
  • Funder:
  • Grant ID:
  • Project Title: EU Grant
  • Funder:
  • Grant ID:
  • Project Title: Bundesamt für Bildung und Wissenschaft
  • Funder: SNSF
  • Grant ID:
  • Project Title: Swiss National Science Foundation
  • Funder:
  • Grant ID:
  • Project Title: URPP "Integrative Human Physiology"
  • Funder:
  • Grant ID:
  • Project Title: Novartis Research Foundation
  • Funder:
  • Grant ID:
  • Project Title: Kanton of Zurich
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  • Language: English
  • Description: Nationallizenz 142-005
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