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

Abstract

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]Ϫ/Ϫ ) 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 Ϫ/Ϫ 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 Ϫ/Ϫ 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 H 2 O 2 -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.

Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages

“…These conclusions were drawn from studies where factors that promoted atherosclerosis, such as oxidized LDL, hyperglycemia, and H 2 O 2 -stimulated PARP activity (47)(48)(49)(50). PARP-1 was activated within atherosclerotic plaques of ApoE Ϫ/Ϫ mice fed a high fat diet (51). PARP-1 deletion, on the other hand, reduced atherosclerotic lesion formation in high fat diet-fed ApoE Ϫ/Ϫ mice (52), and PARP catalytic inhibitors reduced atherosclerotic plaque burden in mouse models of atherosclerosis (53).…”

PDZK1 Is a Novel Factor in Breast Cancer That Is Indirectly Regulated by Estrogen through IGF-1R and Promotes Estrogen-Mediated Growth

“…Stained slides were scanned using the ×40 objective with a Hamamatsu NanoZoomer (Hamamatsu, Bridgewater, NJ, USA). Immunoreactivity was analyzed by using Image-Pro Plus Version 6.0 software (Media Cybernetics, Rockville, MD, USA) as described previously (9,10). The measurement parameters included density mean, area sum and integrated optical density.…”

“…For immunofluorescence, cells were seeded on chamber slides and treated as described in the figure legends. Cells were then fixed, permeabilized and stained with antibodies to PDZK1 (Abcam, Cambridge, MA, USA) and with 4′-6-diamidino-2-phenylindole essentially as described (10). Cells were then examined with a Nikon fluorescence microscope.…”

Signaling Mechanism of Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Inflammatory Diseases

“…57 An imbalance of tissue inhibitor of metalloproteinases and matrix metalloproteinases in the extracellular matrix may constitute a critical contributing factor to atherogenesis. Boulares and coworkers 58,59 found that PARP-1 inhibition provides stability to atherosclerotic plaques associated with increased expression of tissue inhibitor of metalloproteinases 2, decreased activity of matrix metalloproteinase 9, and extracellular matrix degradation in a high-fat, diet-induced, dyslipidemic, dilated cardiomyopathy model. Rheumatoid arthritis is characterized as inflammation with synovial hyperplasia, pannus formation, and progressive destruction of cartilage and bone.…”