This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Ischemic heart disease is the generic designation for a group of closely related syndromes resulting from myocardial ischemia-an imbalance between the supply and demand for oxygenated blood. Up until recently, the pathogenesis was believed to be due to reduction in coronary blood flow due to atherosclerotic coronary artery obstruction. Now we know it is much more complicated. The pathogenesis of atherosclerosis is now thought to include endothelial response to injury and has been compared to chronic inflammation of the vascular wall. It appears that lipid-laden macrophages brought to the vascular wall due to endothelial activation play a role in the stability of the atherosclerotic plaque;rupture of the plaque due to release of matrix metalloproteinases from the macrophages results in exposure of the subintimal space which results in thrombus formation and obstruction (1). Recently, it has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGA-CoA) inhibitors, such as the statins, which are used to treat hypercholesterolemia, also attenuate inflammation of the vascular wall independently of their lipid lowering effects (2). Our long-range goal is to uncover the molecular mechanisms of endothelial cell and macrophage activation by mildly modified LDL (LDL) and to determine whether statins inhibit this activation. The overall objective of this project is to identify the signaling processes affected by statin treatment. The central hypothesis is that statins exert their effect on the vascular wall by inhibiting members of the Ras and families of small GTPases, which have been shown to play a role in inflammatory processes. Identification of pathways downstream of Ras proteins may result in alternative treatment modalities specific to endothelial and macrophage activation. The rationale is that once the mechanisms are identified, statins and other inhibitors of signaling pathways (e.g., the phosphatidylinositol 3-kianse PI3Kcould be used to prevent chronic inflammation of the vascular wall.
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