Two critical features of the unstable atheroma are increased mechanical stresses and decreased extracellular matrix integrity. The monocyte/macrophage infiltrates the fibrous cap and promotes extracellular matrix degradation, particularly at regions of high mechanical stress. In the fibrous cap, the macrophage, unlike the circulating monocyte, is subjected to mechanical deformation by extracellular matrix. Despite the convergence of increased mechanical forces and macrophage infiltration at the critical locations of the unstable lesion, little is known about the responses of the macrophage to mechanical stimuli. The overexpression of matrix degrading proteases at these locations raises questions thus far almost completely unexplored: How do macrophages behave in a high mechanical stress environment? Do macrophages respond to mechanical stimuli, and does this response promote matrix degradation? In this proposal, the investigators will describe experiments that will explore the responses of human monocyte-derived macrophages to biaxially uniform mechanical strains, focusing on expression of genes relevant to extracellular matrix degradation. Understanding how the macrophage is regulated by mechanical signals may provide key insight into excess matrix degradation at plaque rupture locations.
The Specific Aims are:
Specific Aim 1. To explore monocyte/macrophages responses to deformation. They will test the hypothesis that human monocyte/macrophages respond to mechanical strain, focusing on known molecular regulators of MMP expression, as well as PU.1, a transactivating factor of the ets family that is an important macrophage differentiation factor.
Specific Aim 2. To test the hypothesis that deformation regulates synthesis and release of matrix metalloproteinases and their inhibitors from monocyte/macrophages.
Specific Aim 3. To test the hypothesis that extracellular matrix components and specific integrin subunits regulate the molecular responses of monocyte/macrophages.
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