PARP1 is required for adhesion molecule expression in atherogenesis.

• 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.

Keyword

Animals

Apolipoproteins E

genetics

metabolism

Atherosclerosis

enzymology

immunology

pathology

prevention & control

Cell Adhesion Molecules

metabolism

Cholesterol

blood

Disease Models

Animal

E-Selectin

metabolism

Enzyme Inhibitors

pharmacology

Inflammation

enzymology

immunology

pathology

prevention & control

Inflammation Mediators

blood

Macrophages

pathology

Male

Mice

Mice

Inbred C57BL

Mice

Knockout

Necrosis

Nitric Oxide Synthase Type II

metabolism

P-Selectin

metabolism

Phenanthrenes

pharmacology

Poly(ADP-ribose) Polymerases

antagonists & inhibitors

genetics

metabolism

T-Lymphocytes

pathology

Vascular Cell Adhesion Molecule-1

metabolism

Publication and Content Type

ref (subject category)

art (subject category)