Genomes and Genes
Group V Secretory Phospholipase A2 in Atherosclerosis
Principal Investigator: Nancy R Webb
Abstract: [unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable]
Funding Period: 2003-04-01 - 2008-09-30
more information: NIH RePORT
- Thematic review series: The immune system and atherogenesis. Cytokine regulation of macrophage functions in atherogenesisAlan Daugherty
Cardiovascular Research Center, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
J Lipid Res 46:1812-22. 2005..There will be an emphasis on the role of cytokines in regulating lipid metabolism by macrophages. We will provide an overview of the major findings in cell culture and then put these in the context of in vivo studies...
- Group V secretory phospholipase A2-modified low density lipoprotein promotes foam cell formation by a SR-A- and CD36-independent process that involves cellular proteoglycansBoris B Boyanovsky
Department of Internal Medicine and Veterans Affairs Medical Center, Graduate Center for Nutritional Sciences, University of Kentucky Medical Center, Lexington, Kentucky 40536 0200, USA
J Biol Chem 280:32746-52. 2005..Our data point to a physiological modification of LDL that has the potential to promote macrophage foam cell formation independent of scavenger receptors...
- Group v secretory phospholipase A2 promotes atherosclerosis: evidence from genetically altered miceMeredith A Bostrom
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY, USA
Arterioscler Thromb Vasc Biol 27:600-6. 2007..However, there is no direct evidence that this enzyme promotes atherogenic processes in vivo...
- HDL cholesterol transport during inflammationDeneys R van der Westhuyzen
Department of Internal Medicine, Cardiovascular Research Center and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
Curr Opin Lipidol 18:147-51. 2007....
- Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A2-modified LDLBoris B Boyanovsky
Department of Internal Medicine, Endocrinology Division, University of Kentucky Medical Center, Lexington, KY 40536, USA
J Lipid Res 50:641-50. 2009..Taken together, our data point to a novel role for syndecan-4 in mediating the uptake of GV-LDL, a process implicated in atherosclerotic lesion progression...
- The capacity of group V sPLA2 to increase atherogenicity of ApoE-/- and LDLR-/- mouse LDL in vitro predicts its atherogenic role in vivoBoris Boyanovsky
Department of Internal Medicine, University of Kentucky Medical Center, Lexington, KY 40536 0200, USA
Arterioscler Thromb Vasc Biol 29:532-8. 2009..Consistent with this, gain and loss of function studies demonstrated that GV sPLA(2) promotes atherosclerosis in LDLR(-/-) mice. The current study investigates whether GV sPLA(2) promotes atherosclerotic processes in apoE(-/-) mice...