MMP-9 AS A PROINFLAMMATORY REGULATOR IN ATHEROGENESIS

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DESCRIPTION (provided by applicant): Numerous studies examining atherosclerotic lesions from human and animal models have established the central role of the macrophage in atherosclerosis. Despite these observations, it is still unclear what changes within the lesions result in plaque rupture that is responsible for the majority of clinical manifestations of atherosclerosis, We have recently shown for the first time that overexpression of auto-activated MMP-9 in macrophages of pre-existing lesions of ApoE null mice is sufficient to induce plaque rupture. This proposal will utilize this model to correlate changes in cardiovascular function monitored every 2 weeks with cellular and molecular changes in lesion progression. We will also examine the role of different factors known to regulate MMP-9 activity in macrophages, including oxidative stress that has been linked to disease progression. Finally, we have identified novel cell surface substrates of MMP-9 in a macrophage-based proteomics analysis. We will characterize the nature and biological significance of MMP-9 cleavage of these novel inflammatory substrates in vitro and in vivo.