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](-/-)) 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-kappaB 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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Active Transport, Cell Nucleus / drug effects*
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Animals
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Aortic Diseases / drug therapy
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Aortic Diseases / enzymology
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Aortic Diseases / etiology
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Aortic Diseases / genetics
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Aortic Diseases / pathology
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Apoptosis
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Atherosclerosis / drug therapy*
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Atherosclerosis / enzymology
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Atherosclerosis / etiology
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Atherosclerosis / genetics
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Atherosclerosis / pathology
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Chemokine CCL2 / biosynthesis
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Chemokine CCL2 / genetics
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Cholesterol / blood
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Collagen / biosynthesis
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Crosses, Genetic
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Diet, Atherogenic
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Drug Evaluation, Preclinical
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Foam Cells / pathology*
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Gene Expression Regulation / drug effects
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Genotype
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Hydrogen Peroxide / pharmacology
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Hypercholesterolemia / blood
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Hypercholesterolemia / complications
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Hypercholesterolemia / genetics
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Hypertriglyceridemia / blood
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Hypertriglyceridemia / complications
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Hypertriglyceridemia / genetics
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Isoquinolines / pharmacology
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Isoquinolines / therapeutic use*
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Lipopolysaccharides / pharmacology
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Macrophages, Peritoneal / drug effects*
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / metabolism*
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Necrosis
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Oxidative Stress
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Poly Adenosine Diphosphate Ribose / physiology
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Poly(ADP-ribose) Polymerase Inhibitors*
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / physiology
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Specific Pathogen-Free Organisms
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Thiophenes / pharmacology
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Thiophenes / therapeutic use*
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Tissue Inhibitor of Metalloproteinase-2 / metabolism
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Triglycerides / blood
Substances
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Apolipoproteins E
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Ccl2 protein, mouse
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Chemokine CCL2
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Isoquinolines
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Lipopolysaccharides
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NF-kappa B
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Poly(ADP-ribose) Polymerase Inhibitors
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Thiophenes
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Triglycerides
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thieno(2,3-c)isoquinolin-5-one
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Tissue Inhibitor of Metalloproteinase-2
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Poly Adenosine Diphosphate Ribose
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Collagen
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Cholesterol
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Hydrogen Peroxide
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Poly(ADP-ribose) Polymerases