多聚ADP核糖合成酶抑制剂降低高同型半胱氨酸血症诱发ApoE-/-小鼠动脉粥样硬化斑块面积

Poly （ADP-Ribose） polymerase inhibition decreases atherosclerotic lesion size in ApoE-/- mice with hyperhomocysteinemia

目的：检测多聚ADP核糖合成酶[Poly（ADP-ribose） polymerase,PARP]抑制剂3-aminobenzamide（3-AB）是否能够降低由高同型半胱氨酸血症（Hyperhomocysteinemia,Hhcy）诱发ApoE-/-小鼠动脉粥样硬化的斑块面积。方法：健康6周龄雄性ApoE-/-小鼠随机分为普通饮食组（n=30）或高甲硫氨酸饮食组（n=30）,每组再分别给予隔天腹腔注射10mg/kg3-AB（n=20）或0.9%氯化钠（n=20）,持续12周。12周末,检测血脂及血浆同型半胱氨酸（homocysteine,Hcy）含量,分离心脏及主动脉,测量斑块面积,检测斑块局部NADPH氧化酶亚单位p47phox含量、PARP活性及表达。结果：高甲硫氨酸饮食诱导ApoE-/-小鼠产生Hhcy,促进氧化应激相关p47phox表达及PARP活化,显著增加斑块面积;PARP抑制剂3-AB虽然对普食组ApoE-/-小鼠抑制效果不明显,却能在不影响血浆Hcy和脂质含量的情况下,抑制Hhcy诱导的PARP活化,显著降低其粥样斑块面积达40%。结论：PARP抑制剂3-AB显著降低Hhcy诱导的ApoE-. ／一小鼠动脉粥样硬化斑块面积，可作为有效抑制粥样斑块进程的治疗方法之一。

Objectives：To explore whether Poly （ADP-ribose） polymerase （PARP） inhibitor 3-aminobenzamide （3 AB） decreases the atherosclerotic plaque size in an hyperhomocysteinemia （Hhey）-induced experimental model with atherosclerosis. Methods：Si^week-old homozygous apolipoprotein E-deficient （ApoE/-） male mice fed with normal diet or high methionine-diet were randomly received intraperitoneal injections of 10 mg/kg 3-AB dissolved in PBS, or physiological saline every other day for 12 weeks. Plasma homocysteine （Hcy） levels and lipids con- tents were measured. Atherosclerotic lesion sizes, the phosphorylation of p47phox subunit of NADPH oxidase and the expression of PARP protein and PARP activity were detected. Results：ApoE-/ mice fed with high methionine- diet generated Hhcy, which could promote the oxidative stress-associated the phosphorylation of p47phox and PARP activation, and increase the atherosclerotic lesion size significantly. Although PARP inhibition by 3-AB did not markedly inhibit the plaque development in ApoE-/- mice with spontaneous hyperlipidemia fed with normal di et, it significantly reduced atheroselerotic lesion size by 40% in Hhcy-induced atherosclerosis without affecting plasma homocysteine levels and lipid contents, effectively suppressed the PARP activation. Conclusions： Our re- suits suggest that PARP inhibition attenuates the atherosclerotic plaque size in the hyperhomocysteinemic condi tions, indicates 3-AB may prove beneficial for the treatment of atherosclerosis.