Project 1: Dynamic Interplay of Eicosanoids in Cardiovascular Biology Products of the cyclooxygenase (C0X)-2 have been directly implicated in both inflammatory and thrombotic disease. However, predominant products of the COX enzymes vary between cells and have contrasting biology. The microsomal PGE synthase (mPGES)-1 has emerged as a drug target alternative to COX-2. A combined genetic and pharmacological approach will be taken to elucidate the roles of these enzymes in discrete cells and to assess the impact of COX-2 perturbation on biological networks. Versatile biomarkers of inflammation and oxidant stress will be combined in lipidomic analyses to integrate the divergent impact of cell specific enzyme disruptions on atherosclerosis in vivo with mechanistic studies in vitro.
In Specific Aim 1 we shall assess the importance of COX-2 in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in regulating (i) the response to thrombogenic stimuli in large and small blood vessels and (ii) blood pressure homeostasis. Analysis of these phenotypes in mice deficient in discrete prostanoid receptors and cell specific deletions of COX-2 will be compared with the effects of global disruption of COX -2 function using genetic and pharmacological approaches.
In Specific Aim 2 we shall seek to elucidate the controversy surrounding COX-2 inhibition and atherosclerosis. The impact of induced global deletion of the enzyme will be assessed at varied stages of disease evolution, as will the distinct roles of EC, VSMC and macrophage COX-2 on prostanoid biosynthesis, the inflammatory response and lesional progression and morphology. Multiple tissues will be harvested from these and other mice with discrete deletions of COX-2 to determine how enzyme perturbation might impact on biological networks relevant to inflammation and how this might be influenced by age, gender and diet.
In Specific Aim 3 we will utilize both a novel selective inhibitor of mPGES-1 and cell specific deletions ofthe enzyme to address the hypothesis that contrasting, functionally relevant patterns of substrate rediversion might ocpur at different stages of disease evolution. Unbiased analyses will be performed of the comparative impact of mPGES-1 vs COX-2 deletion on the response to inflammatory stimuli in discrete cell types. Finally, in Specific Aim 4, we shall assess the effect of deleting COX-2 or mPGES-1 in discrete cells - that differ in their primary prostanoids or rediversion products - on the response to vascular injury. We shall also determine whether systemic hypertension might exacerbate the impact of deleting either enzyme in cardiomyocytes on heart function and rhythm.
These studies will elucidate the cardiovascular biology of both COX-2 and mPGES-1 with particular relevance to atherosclerosis. This is relevant to development of strategies to manage scientifically the cardiovascular risk while conserving the benefit of NSAIDs and in the prediction of the relative cardiovascular safety of inhibitors of mPGES-1.
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