Poly (ADP-Ribose) Polymerase Inhibition Attenuates Atherosclerotic Plaque Development in ApoE-/- Mice with Hyperhomocysteinemia

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 atherosclerotic 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-aminobenzamide (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 factors 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 inflammatory 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-kappa B translocation and subsequent expression of inflammatory factors.