Fulltext

PARP1 is required for adhesion molecule expression in atherogenesis

von Lukowicz, Tobias ; Hassa, Paul O. ; Lohmann, Christine ; Borén, Jan ; Braunersreuther, Vincent ; Mach, François ; Odermatt, Bernhard ; Gersbach, Monika ; Camici, Giovanni G. ; Stähli, Barbara E. ; Tanner, Felix C. ; Hottiger, Michael O. ; Lüscher, Thomas F. ; Matter, Christian M.

In: Cardiovascular Research, 2008, vol. 78, no. 1, p. 158-166

Add to personal list
    Title
    • PARP1 is required for adhesion molecule expression in atherogenesis
    Author
    • von Lukowicz, Tobias. Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland
    • Hassa, Paul O.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland
    • Lohmann, Christine. Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland
    • Borén, Jan. Wallenberg Laboratory, Sahlgrenska Academy at Goteborg University, Goteborg, Sweden
    • Braunersreuther, Vincent. Division of Cardiology, University Hospital Geneva, Geneva, Switzerland
    • Mach, François. Division of Cardiology, University Hospital Geneva, Geneva, Switzerland
    • Odermatt, Bernhard. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
    • Gersbach, Monika. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland
    • Camici, Giovanni G.. Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland
    • Stähli, Barbara E.. Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland
    • Tanner, Felix C.. Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland
    • Hottiger, Michael O.. Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Zurich, Switzerland
    • Lüscher, Thomas F.. Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland
    • Matter, Christian M.. Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Cardiovascular Research, 2008, vol. 78, no. 1, p. 158-166. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:291728
    Summary
    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