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

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10 mg/kg 3-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-/-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.

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

Objectives:To explore whether Poly (ADP-ribose) polymerase (PARP) inhibitor 3-aminobenzamide (3-AB) decreases the atherosclerotic plaque size in an hyperhomocysteinemia (Hhcy)-induced experimental model with atherosclerosis. Methods:Six-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 contents 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 diet, it significantly reduced atherosclerotic lesion size by 40% in Hhcy-induced atherosclerosis without affecting plasma homocysteine levels and lipid contents, effectively suppressed the PARP activation. Conclusions:Our results suggest that PARP inhibition attenuates the atherosclerotic plaque size in the hyperhomocysteinemic conditions, indicates 3-AB may prove beneficial for the treatment of atherosclerosis.