Poly (ADP-Ribose) polymerase inhibition attenuates atherosclerotic plaque development in ApoE-/- mice with hyperhomocysteinemia.
OBJECTIVE
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).


CONCLUSIONS
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.
Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, China.
Jiang-Jiao
JJ
Xie
Xian
X
Yu
Yu-Hua
YH
Liao
Jian
J
Chen
Rui
R
Yao
Yong
Y
Chen
Meng-Yang
MY
Liao
Ying-Jun
YJ
Ding
Ting-Ting
TT
Tang
Xiang
X
Cheng
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000150:complications / Q000517:prevention & control*; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D017931:DNA Primers; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000150:complications*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016133:Polymerase Chain Reaction
D001057:Apolipoproteins E; D001549:Benzamides; D017931:DNA Primers; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases