title: PARP1 is required for adhesion molecule expression in atherogenesis.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors: Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland.
authors: Tobias
authors: T
authors: von Lukowicz
authors: Paul O
authors: PO
authors: Hassa
authors: Christine
authors: C
authors: Lohmann
authors: Jan
authors: J
authors: Borén
authors: Vincent
authors: V
authors: Braunersreuther
authors: François
authors: F
authors: Mach
authors: Bernhard
authors: B
authors: Odermatt
authors: Monika
authors: M
authors: Gersbach
authors: Giovanni G
authors: GG
authors: Camici
authors: Barbara E
authors: BE
authors: Stähli
authors: Felix C
authors: FC
authors: Tanner
authors: Michael O
authors: MO
authors: Hottiger
authors: Thomas F
authors: TF
authors: Lüscher
authors: Christian M
authors: CM
authors: Matter
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000097:blood; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D019007:P-Selectin; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019010:Vascular Cell Adhesion Molecule-1; D002784:Cholesterol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases