Group V sPLA2 in Atherosclerosis

Grants and Contracts Details

Description

A critical event in early atherogenesis is the retention of low-density lipoprotein (LDL) particles in the subendothelium through their binding to intimal proteoglycans. These retained lipoprotein particles are exposed to several modifying enzymes in the arterial wall, including lipases, oxidizing enzymes, and proteases. A multitude of biological responses to such modified LDL, including the recruitment and lipid loading of macrophages, leads to the initiation and progression of atherosclerosis. The extracellular matrix (ECM) appears to play an active role in this process by not only mediating the retention of LDL particles, but by also modulating the activity of various enzymes towards LDL. Thus, in regions where LDL is being accumulated, the co-localization of LDL, ECM, and LDL modifying enzymes leads to a self-perpetuating cascade of events that culminates in atherosclerosis. The identification and characterization of molecules and the manner in which they interact to contribute to this process, is central to our understanding the mechanisms that underlie susceptibility to lesion formation. This proposal aims to study a novel form of secretory phospholipase A2, Group V sPLA2, which we now show is present in human and mouse atherosclerotic lesions specifically associated with macrophages. We hypothesize that Group V sPLA2and LDL in the proximity of macrophages leads to the localized production of aggregated and/or fused lipoprotein particles, which consequently leads to foam cell formation. To test this hypothesis, the following specific aims are proposed: Specific Aim 1): To test the hypothesis that Group V sPLA2 produces modifications in LDL particles that lead to increased uptake by macrophages. This will be accomplished by analyzing LDL particles after hydrolysis by Group V sPLA2 to determine particle composition, density, and extent of aggregation and/or fusion; quantifying the effect of Group V sPLA2 hydrolysis on the delivery of LDL lipid to macrophages, and determining whether other factors in the arterial subendothelium, namely sphingomyelinase and ECM, promote Group V sPLA2-mediated effects. Specific Aim 2): To test the hypothesis that macrophage expression of Group V sPLA2 in the vessel wall results in increased atherosclerosis. This will be achieved by transplanting fetal liver hematopoetic stem cells over-expressing wild-type Group V sPLA2, or a mutant form of the enzyme that is deficient in proteglycan binding, into LDL receptor-/- mice. Measuring lesion size and cholesterol/cholesterol ester content will assess the extent of atherosclerosis.
StatusFinished
Effective start/end date4/1/039/30/08

Funding

  • National Heart Lung and Blood Institute: $1,811,951.00

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