A Murine Model for Inhibition of Farnesyltransferase

描述(由申请人提供)：炎症在动脉粥样硬化发展的所有阶段都被认为是一个关键的组成部分。血管和循环血细胞分泌的多种炎性细胞因子，包括MCP-1、M-CSF、IL-6、IL-10、干扰素-γ、转化生长因子-β1，已被证明在动脉粥样硬化病变的形成和发展中起作用。最近的数据表明，HMG-CoA还原酶抑制剂(他汀类药物)对动脉粥样硬化患者的一些有益影响可能部分是通过直接影响一个或多个这些细胞因子的表达来实现的，而与其降低胆固醇的全身作用无关。具体地说，这些药物在减少中风方面的效果是这些药物存在临床相关的胆固醇非依赖性作用的最好证据。我们的初步数据表明，他汀类药物调节了人血管平滑肌细胞和巨噬细胞中活性的转化生长因子-β1(aTGF-β1)的表达，巨噬细胞是动脉粥样硬化斑块的常见细胞成分。我们的结果得到了其他小组的证实，表明他汀类药物对直接在血管壁内的细胞上调节各种细胞因子的表达有影响。为了直接分析他汀类药物对血管壁内细胞的作用，独立于其对胆固醇代谢的全身性影响，我们建议建立转基因动物，并在动脉粥样硬化斑块中激活的巨噬细胞内局部靶向表达显性负突变的法尼基转移酶蛋白。我们推测，他汀类药物在减少脑血管事件方面的多效性益处的一部分，可能是通过其局部调节各种细胞因子的表达而实现的，而不依赖于任何全身降胆固醇的效果。

DESCRIPTION (provided by applicant): Inflammation has been recognized as a key component of atherosclerotic at all stages of its development. Multiple inflammatory cytokines, including MCP-1, M-CSF, IL-6, IL-10, IFN-y, TGF-P1 secreted by vascular and circulating blood cells, have been shown to have a role in both atherosclerotic lesion formation and progression. Recent data suggest that some of the beneficial affects of HMG-CoA reductase inhibitors (statins) in patients with atherosclerosis may in part be mediated through a direct effect on expression of one or more of these cytokines, independent of its systemic effect on cholesterol reduction. Specifically the effect of these agents on reduction of stroke are the best available evidence fro the presence of clinically relevant cholesterol-independent effects of these drugs. Our preliminary data suggest that statins modulate active TGF-P1 (aTGF-pl) expression in both human vascular smooth muscle cells (HVSMC) and macrophages, the common cellular constituent of atherosclerotic plaque. Our results are corroborated by other groups demonstrating an effect of statins on modulating expression of various cytokines directly on the cells within the vessel wall. To dissect out the role of statins on the cells within the vessel wall directly, independent of its systemic effects on cholesterol metabolism, we propose generation of transgenic animals with targeted expression of a dominant negative mutated farnesyltransferase protein locally within the activated macrophages in the atherosclerotic plaque. We postulate that part of the pleiotropic benefit of statins specifically in reduction of cerebrovascular events may be mediated through its effect on modulating expression of various cytokines locally independent of any systemic effects on cholesterol reduction.