PARP1 is required for adhesion molecule expression in atherogenesis.
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.
von Lukowicz
Tobias
T
Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiology, Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland.
Hassa
Paul O
PO
Lohmann
Christine
C
Borén
Jan
J
Braunersreuther
Vincent
V
Mach
François
F
Odermatt
Bernhard
B
Gersbach
Monika
M
Camici
Giovanni G
GG
Stähli
Barbara E
BE
Tanner
Felix C
FC
Hottiger
Michael O
MO
Lüscher
Thomas F
TF
Matter
Christian M
CM
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
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