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Cardiovascular Research Advance Access first published online on December 18, 2007
This version [Corrected Proof] published online on January 23, 2008
Cardiovascular Research, doi:10.1093/cvr/cvm110
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

PARP1 is required for adhesion molecule expression in atherogenesis

Tobias von Lukowicz1,2, Paul O. Hassa3, Christine Lohmann1,2, Jan Borén4, Vincent Braunersreuther5, François Mach5, Bernhard Odermatt6, Monika Gersbach3, Giovanni G. Camici1,2, Barbara E. Stähli1,2, Felix C. Tanner1,2, Michael O. Hottiger3, Thomas F. Lüscher1,2 and Christian M. Matter1,2,*

1 Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland
2 Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
3 Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland
4 Wallenberg Laboratory, Sahlgrenska Academy at Goteborg University, Goteborg, Sweden
5 Division of Cardiology, University Hospital Geneva, Geneva, Switzerland
6 Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland

* Corresponding author. Tel: +41 44 635 6467; fax: +41 44 635 6827. E-mail address: cmatter{at}physiol.uzh.ch

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 ≥ 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 ≥ 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.

KEYWORDS Atherosclerosis; PARP; Inflammation; Macrophages; Adhesion molecule

Time for primary review: 20 days


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