Abstract 1131: PARP1 is required for Adhesion Molecule Expression in Atherogenesis
Objective - Atherosclerosis is a chronic inflammatory disease resulting from the interaction between modified lipoproteins, activated endothelial cells, macrophages, T-cells, and elements of the arterial wall. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that plays a role in acute inflammatory responses of cells and organs.
Methods and Results - 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). Pharmacological PARP inhibition using PJ34 or PARP1 deletion reduced PARP activity and diminished expression of inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), P-, and E-selectin (see Figure⇓). 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).
Conclusions - Our data provide pharmacologic and genetic evidence that endogenous PARP1 is required for the development of atherosclerosis in vivo by increasing adhesion molecules due to endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising novel therapeutic target in atherosclerosis.