A Murine Model for Inhibition of Farnesyltransferase

描述（由申请人提供）：炎症已被认为是动脉粥样硬化所有发展阶段的关键组成部分。多种炎性细胞因子，包括由血管和循环血细胞分泌的MCP-1、M-CSF、IL-6、IL-10、IFN-γ、TGF-β 1，已显示在动脉粥样硬化病变形成和进展中具有作用。最近的数据表明，HMG-CoA还原酶抑制剂（他汀类药物）在动脉粥样硬化患者中的一些有益作用可能部分是通过对一种或多种这些细胞因子表达的直接作用介导的，与其对胆固醇降低的全身作用无关。具体而言，这些药物对减少卒中的作用是这些药物存在临床相关胆固醇非依赖性作用的最佳可用证据。我们的初步数据表明，他汀类药物调节人血管平滑肌细胞（HVSMC）和巨噬细胞（动脉粥样硬化斑块的常见细胞成分）中活性TGF-β 1（aTGF-β 1）的表达。我们的结果得到了其他研究组的证实，这些研究组证明了他汀类药物对直接调节血管壁内细胞上各种细胞因子表达的影响。为了直接剖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作用，我们建议在动脉粥样硬化斑块中的活化巨噬细胞内局部靶向表达显性阴性突变法尼基转移酶蛋白的转基因动物。我们推测，他汀类药物特异性减少脑血管事件的部分多效性获益可能是通过其调节各种细胞因子表达的作用介导的，而不依赖于对胆固醇降低的任何全身作用。

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.