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PARP1 is required for adhesion molecule expression in atherogenesis

von Lukowicz, Tobias
Hassa, Paul O.
Lohmann, Christine
Borén, Jan
Odermatt, Bernhard
Gersbach, Monika
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Published in Cardiovascular research. 2008, vol. 78, no. 1, p. 158-66
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.
Keywords AnimalsApolipoproteins E/genetics/metabolismAtherosclerosis/enzymology/immunology/pathology/prevention & controlCell Adhesion Molecules/metabolismCholesterol/bloodDisease Models, AnimalE-Selectin/metabolismEnzyme Inhibitors/pharmacologyInflammation/enzymology/immunology/pathology/prevention & controlInflammation Mediators/bloodMacrophages/pathologyMaleMiceMice, Inbred C57BLMice, KnockoutNecrosisNitric Oxide Synthase Type II/metabolismP-Selectin/metabolismPhenanthrenes/pharmacologyPoly(ADP-ribose) Polymerases/antagonists & inhibitors/genetics/metabolismT-Lymphocytes/pathologyVascular Cell Adhesion Molecule-1/metabolism
PMID: 18093987
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Other version: http://cardiovascres.oxfordjournals.org/cgi/content/full/78/1/158
Research groups Biologie du myocarde (22)
L'athérosclérose et ses complications cliniques (591)
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VON LUKOWICZ, Tobias et al. PARP1 is required for adhesion molecule expression in atherogenesis. In: Cardiovascular research, 2008, vol. 78, n° 1, p. 158-66. doi: 10.1093/cvr/cvm110 https://archive-ouverte.unige.ch/unige:2144

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Deposited on : 2009-06-23

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