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(Circulation. 2007;115:2442-2450.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Poly(ADP-Ribose) Polymerase Inhibition Reduces Atherosclerotic Plaque Size and Promotes Factors of Plaque Stability in Apolipoprotein E–Deficient Mice

Effects on Macrophage Recruitment, Nuclear Factor-B Nuclear Translocation, and Foam Cell Death

Karine Oumouna-Benachour, PhD^*; Chetan P. Hans, PhD^*; Yasuhiro Suzuki, MD, PhD; Amarjit Naura, PhD; Rahul Datta, BS; Souad Belmadani, PhD; Kenneth Fallon, MD; Cooper Woods, PhD; A. Hamid Boulares, PhD

From the Departments of Pharmacology (K.O.-B., C.P.H., Y.S., A.N., R.D., S.B., A.H.B.) and Pathology (K.F.), Louisiana State University Health Sciences Center; and Cardiovascular Division, Ochsner Clinic Foundation (C.W.), New Orleans, La.

Correspondence to A. Hamid Boulares, PhD, Louisiana State University Health Sciences Center, Department of Pharmacology, 1901 Perdido St, New Orleans, LA 70112. E-mail hboulr{at}lsuhsc.edu

Received October 5, 2006; accepted February 8, 2007.

Background— Poly(ADP-ribose) polymerase (PARP) was suggested to play a role in endothelial dysfunction that is associated with a number of cardiovascular diseases. We hypothesized that PARP may play an important role in atherogenesis and that its inhibition may attenuate atherosclerotic plaque development in an experimental model of atherosclerosis.

Methods and Results— Using a mouse (apolipoprotein E [ApoE]^–/–) model of high-fat diet–induced atherosclerosis, we demonstrate an association between cell death and oxidative stress–associated DNA damage and PARP activation within atherosclerotic plaques. PARP inhibition by thieno[2,3-c]isoquinolin-5-one reduced plaque number and size and altered structural composition of plaques in these animals without affecting sera lipid contents. These results were corroborated genetically with the use of ApoE^–/– mice that are heterozygous for PARP-1. PARP inhibition promoted an increase in collagen content, potentially through an increase in tissue inhibitor of metalloproteinase-2, and transmigration of smooth muscle cells to intima of atherosclerotic plaques as well as a decrease in monocyte chemotactic protein-1 production, all of which are markers of plaque stability. In PARP-1^–/– macrophages, monocyte chemotactic protein-1 expression was severely inhibited because of a defective nuclear factor-B nuclear translocation in response to lipopolysaccharide. Furthermore, PARP-1 gene deletion not only conferred protection to foam cells against H₂O₂-induced death but also switched the mode of death from necrosis to apoptosis.

Conclusions— Our results suggest that PARP inhibition interferes with plaque development and may promote plaque stability, possibly through a reduction in inflammatory factors and cellular changes related to plaque dynamics. PARP inhibition may prove beneficial for the treatment of atherosclerosis.

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