Beller Carsten J, Radovits Tamás, Kosse Jens, Gerö Domokos, Szabó Csaba, Szabó Gábor
Department of Cardiac Surgery, University of Heidelberg, Germany.
J Vasc Surg. 2006 Apr;43(4):824-30. doi: 10.1016/j.jvs.2005.11.021.
In a rat model of endarterectomy, we investigated the potential role of the peroxynitrite-poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) pathway in neointima formation and the effect of pharmacologic inhibition of PARP on vascular remodeling.
Carotid endarterectomy was performed in male Sprague-Dawley rats by incision of the left carotid artery with removal of intima. Three groups were studied: sham-operated rats (n = 10), control rats with endarterectomy (n = 10) or rats with endarterectomy treated with the PARP inhibitor, INO-1001 (5 mg/kg daily) postoperatively (n =10). After 21 days, neointima formation and vascular remodeling were assessed.
Immunohistochemistry analysis demonstrated activation of the peroxynitrite-PARP pathway with significant staining for nitrotyrosine, poly(ADP-ribose), and nuclear translocation of apoptosis-inducing factor (AIF) in the neointima of the control group. Treatment with INO-1001 significantly reduced the neointima area (0.024 mm2 +/- 0.019 mm2 vs 0.089 mm2 +/- 0.033 mm2 in the control group), the neointima/media thickness ratio (0.81 +/- 0.05 vs 2.76 +/- 1.57 in the control group), and the inflammation score (0.1 +/- 0.07 vs 0.3 +/- 0.12 in the control group) after endarterectomy.
Pharmacologic inhibition of PARP with INO-1001 may be a new concept to prevent neointimal hyperplasia after endarterectomy.
在大鼠动脉内膜切除术模型中，我们研究了过氧亚硝酸盐-聚（二磷酸腺苷[ADP]-核糖）聚合酶（PARP）途径在新生内膜形成中的潜在作用，以及PARP的药理抑制对血管重塑的影响。
对雄性Sprague-Dawley大鼠进行左颈动脉切开并切除内膜的动脉内膜切除术。研究了三组：假手术大鼠（n = 10）、接受动脉内膜切除术的对照大鼠（n = 10）或术后用PARP抑制剂INO-1001（每日5 mg/kg）治疗的接受动脉内膜切除术的大鼠（n = 10）。21天后，评估新生内膜形成和血管重塑情况。
免疫组织化学分析显示，对照组新生内膜中过氧亚硝酸盐-PARP途径激活，硝基酪氨酸、聚（ADP-核糖）染色显著，凋亡诱导因子（AIF）核转位。用INO-1001治疗显著降低了动脉内膜切除术后的新生内膜面积（0.024 mm2±0.019 mm2 vs对照组的0.089 mm2±0.033 mm2）、新生内膜/中膜厚度比（0.81±0.05 vs对照组的2.76±1.57）和炎症评分（0.1±0.07 vs对照组的0.3±0.12）。
用INO-1001对PARP进行药理抑制可能是预防动脉内膜切除术后新生内膜增生的一个新概念。
