George Jacob, Sack Jessica, Barshack Iris, Keren Pnina, Goldberg Iris, Haklai Roni, Elad-Sfadia Galit, Kloog Yoel, Keren Gad
Department of Cardiology and the Cardiovascular Research Laboratory,Tel Aviv Sourasky Medical Center, Tel Aviv University, Sackler School of Medicine, Israel.
Arterioscler Thromb Vasc Biol. 2004 Feb;24(2):363-8. doi: 10.1161/01.ATV.0000112021.98971.f0. Epub 2003 Dec 11.
Neointimal formation with and without previous vascular injury is common after balloon dilation and in transplant arteriosclerosis. It involves proliferation and migration of medial smooth muscle cells and inflammation, processes that are regulated by Ras proteins and their down-stream effectors. Farnesylthiosalicylate (FTS) is a Ras inhibitor that interferes with Ras membrane anchorage and affects Ras proteins in their active state. In the present study, we tested the hypothesis that systemic administration of FTS will suppress intimal thickening in the rat carotid injury model.
The effects of FTS on rat vascular smooth muscle cells (VSMC) and splenocytes proliferation were evaluated in vitro. The in vivo effects of FTS on the neointima of balloon-injured male Wistar rats, treated daily for 2 weeks with FTS (5 mg/kg weight, intraperitoneally) were evaluated by determination of Ras, Ras-GTP, and active ERK levels (3 days after injury), and by quantitative determination of the extent of intimal thickening and immunohistochemistry for Ras, iNOS, NFkB, and Ki-67 (2 weeks after injury). FTS inhibited VSMC and splenocyte proliferation as well as interferon-gamma secretion by splenocytes in a dose-dependent manner. Compared with controls, FTS treatment resulted in a strong decrease in Ras-GTP and active ERK, and it significantly reduced intimal thickening after the injury. Ras expression appeared predominantly at areas of neointima regardless of the treatment group. NFkB and iNOS-positive cell numbers were reduced in sections of FTS treated rats.
FTS appears to act as a potent inhibitor of intimal thickening in a model of experimental arterial injury.
在球囊扩张后以及移植动脉硬化过程中，无论有无先前的血管损伤，新生内膜形成均很常见。它涉及中膜平滑肌细胞的增殖和迁移以及炎症反应，这些过程受Ras蛋白及其下游效应器调控。法尼基硫代水杨酸（FTS）是一种Ras抑制剂，可干扰Ras膜锚定并影响处于活性状态的Ras蛋白。在本研究中，我们检验了以下假设：全身给予FTS将抑制大鼠颈动脉损伤模型中的内膜增厚。
在体外评估了FTS对大鼠血管平滑肌细胞（VSMC）和脾细胞增殖的影响。通过测定Ras、Ras-GTP和活性ERK水平（损伤后3天），以及通过定量测定内膜增厚程度和对Ras、诱导型一氧化氮合酶（iNOS）、核因子κB（NFkB）和Ki-67进行免疫组织化学分析（损伤后2周），评估了FTS对球囊损伤雄性Wistar大鼠新生内膜的体内作用。FTS以剂量依赖性方式抑制VSMC和脾细胞增殖以及脾细胞分泌干扰素-γ。与对照组相比，FTS治疗导致Ras-GTP和活性ERK显著降低，并显著减少损伤后的内膜增厚。无论治疗组如何，Ras表达主要出现在新生内膜区域。FTS治疗大鼠切片中NFkB和iNOS阳性细胞数量减少。
在实验性动脉损伤模型中，FTS似乎是内膜增厚的有效抑制剂。
