Role of PAPP-A in Atherosclerosis

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DESCRIPTION (provided by applicant): This proposal focuses on a newly recognized metalloproteinase in the insulin-like growth factor (IGF) regulatory system in atherosclerosis. IGFs play a critical role in the vascular injury response through their potent effects on cell proliferation, migration, survival and extracellular matrix production within the developing intimal lesion. IGF binding proteins (IGFBPs) produced by vascular cells modulate local IGF bioactivity through their control of IGF interaction with specific cell surface receptors. In vitro studies have implicated an inhibitory IGFBP, IGFBP-4, and a specific IGFBP-4 protease (IGFBP4-ase), so-called pregnancy-associated plasma protein A (PAPP-A), in cellular response to injury, including vascular injury. By cleaving IGFBP-4 in a highly regulated manner, IGFBP4-ase/PAPPA increases the pericellular IGF available for receptor activation. In vivo, IGFBP4-ase/PAPP-A expression is induced in injured coronary arteries paralleling the formation of neointima. Recently, IGFBP4-ase/PAPP-A immunoreactivity was demonstrated in culprit plaques of humans who had died of myocardial infarction, with the most intense staining in the inflammatory shoulder associated with smooth muscle cells, macrophages, and T-lymphocytes. Our overall hypothesis is that IGFBP4- ase/PAPP-A is a key IGF regulatory factor in the vascular response to injury leading to atherosclerosis and promoting plaque vulnerability. Utilizing cultured human cells and genetically engineered mice, the SPECIFIC AIMS of this proposal are to: 1) Determine the mechanisms underlying elevated IGFBP4-ase/PAPP-A in vulnerable plaque. 2) Determine the effect of IGFBP4-ase/PAPP-A deficiency on the development and progression of atherosclerotic plaque. 3) Determine the effect of targeted IGFBP4-ase/PAPP-A expression on the development and progression of atherosclerotic plaque. These studies seek to gain a better understanding of the cellular and molecular biology of atherosclerosis in order to establish a scientific basis for novel strategies to identify and limit plaque development, progression, and instability.