MODIFIED-LDL REGULATES MACROPHAGE PLASMINOGEN ACTIVATION

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The emigration of monocytes from the circulation to a subendothelial position, and their subsequent transformation into cholesteryl ester rich foam cells is one of the earliest recognizable processes in lesion formation. Since macrophages are pluripotent effector-cells, alterations in their function as a consequence of lipid accumulation would have important ramifications regarding vascular biology. In this regard, macrophages possess a scavenger receptor which mediates the uptake of LDL modified in vitro or in vivo. Preliminary studies have demonstrated that ligands of the scavenger receptor stimulate macrophage secretion of plasminogen activator. Macrophage mediated conversion of plasminogen to the broad spectrum protease plasmin has been demonstrated to play a role in tissue destruction at inflammatory loci, tissue remodeling and cell movement. Furthermore, plasmin can alter the biological properties of other hydrolases, growth factors and hormones. In the subendothelial space, unlike in the fluid phase, plasmin can bind extracellular matrix components or cells rendering it insensitive to circulating inhibitors. Consequently, the activation of plasminogen by macrophages could affect the structural integrity of the intima leading to the focal loss of endothelial cells and its sequelae. Therefore, we will investigate the regulation of macrophage-dependent plasminogen activation by modified-LDL in a comprehensive and systematic manner. Soluble and membrane associated plasminogen activator (PA) and PA inhibitor (PAl) activities will be assessed and characterized. We will investigate how lipoprotein modulates the synthesis and secretion of PA and PAl, and the expression of PA and PAl mRNA. We will evaluate macrophage degradation of collagenous and noncollagenous matrix components, including heparin sulfate proteoglycan. The role of membrane and soluble PA in these processes will be investigated. Finally, we will determine how functional status of the macrophage influences their response to lipoprotein challenge. For these purposes, we will study lipo-protein metabolism by macrophage populations induced in vivo with eliciting and activating agents, and cells exposed to defined cytokines in vitro. We will then examine lipo-protein modulation of PA and PAl expression by these stimulated cells. Together, these experiments will provide a comprehensive analysis of the regulation of macrophage plasminogen activation by modified-LDL.