Document Detail


Poly (ADP-Ribose) polymerase inhibition attenuates atherosclerotic plaque development in ApoE-/- mice with hyperhomocysteinemia.
MedLine Citation:
PMID:  19776495     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIM: Hyperhomocysteinemia (Hhcy) is an important and independent risk factor for atherosclerosis. Recent studies have shown that Poly (ADP-ribose) polymerase (PARP) activation may be associated with Hhcy-induced endothelial dysfunction, which is an important mechanism for Hhcy to affect atherosclerotic progress. Thus, we investigated whether PARP inhibitors may attenuate atheroscle-rotic plaque development in an Hhcy-induced experimental animal model with atherosclerosis.METHODS: Six-week-old homozygous apolipoprotein E-deficient (ApoE-/-) male mice fed a normal diet or high methionine diet randomly received intraperitoneal injections of 10 mg/kg 3-aminoben-zamide (3-AB, a PARP inhibitor) dissolved in phosphate-buffered saline (PBS), or physiological saline every other day for 12 weeks. Atherosclerotic lesion sizes and PARP activity were measured. Related inflammatory factors in atherogenesis were investigated by real-time quantitative PCR and Western blot analysis.RESULTS: Our data demonstrated that ApoE-/- mice fed a high methionine diet generated Hhcy, which subsequently increased the atherosclerotic lesion size significantly, promoted oxidative stress-associated DNA damage and PARP activation, then increased the expression of proinflammatory fac-tors within atherosclerotic plaques. Although PARP inhibition by 3-AB did not markedly inhibit plaque development in ApoE-/- mice with spontaneous hyperlipidemia by feeding a normal diet, it significantly reduced the atherosclerotic lesion size by 40% in Hhcy-induced atherosclerosis without affecting plasma homocysteine levels and lipid contents, effectively suppressed PARP activation, and inhibited nuclear translocation of nuclear factor-(kappa)B (NF-(kappa)B) and subsequent production of inflam-matory factors, such as vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattactant protein-1 (MCP-1).CONCLUSION: Our results suggest that PARP inhibition attenuates atherosclerotic plaque development under hyperhomocysteinemic conditions, through the inhibition of PARP activation, nuclear NF-kappaB translocation and subsequent expression of inflammatory factors.
Authors:
Jiang-Jiao Xie; Xian Yu; Yu-Hua Liao; Jian Chen; Rui Yao; Yong Chen; Meng-Yang Liao; Ying-Jun Ding; Ting-Ting Tang; Xiang Cheng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-09-24
Journal Detail:
Title:  Journal of atherosclerosis and thrombosis     Volume:  16     ISSN:  1880-3873     ISO Abbreviation:  J. Atheroscler. Thromb.     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-11-12     Completed Date:  2010-02-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9506298     Medline TA:  J Atheroscler Thromb     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  641-53     Citation Subset:  IM    
Affiliation:
Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apolipoproteins E / genetics,  physiology*
Apoptosis / drug effects
Atherosclerosis / complications,  prevention & control*
Base Sequence
Benzamides / pharmacology*
Blotting, Western
DNA Primers
Enzyme Activation
Enzyme Inhibitors / pharmacology*
Hyperhomocysteinemia / complications*
Male
Mice
Mice, Knockout
NF-kappa B / metabolism
Poly(ADP-ribose) Polymerases / antagonists & inhibitors*,  metabolism
Polymerase Chain Reaction
Chemical
Reg. No./Substance:
0/Apolipoproteins E; 0/Benzamides; 0/DNA Primers; 0/Enzyme Inhibitors; 0/NF-kappa B; 3544-24-9/3-aminobenzamide; EC 2.4.2.30/Poly(ADP-ribose) Polymerases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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