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.
