Atherosclerosis is an inflammatory process that results in the formation of unstable coronary lesions vulnerable to disruption and subsequent thrombosis. Cell adhesion molecules (CAMs) participate in the recruitment of inflammatory cells, in cell-cell and cell-matrix interactions, and in signal transduction within the developing atherosclerotic lesion. CD44 is a widely expressed CAM that serves as a principal receptor for hyaluronan, an extracellular matrix glycosaminoglycan that accumulates in atheroslerotic lesions. CD44 is expressed in a low affinity state on most primary cells but is activated to a high affinity state in the presence of inflammatory stimuli. CD44 has been implicated in a variety of chronic inflammatory responses. We investigated the role of CD44 in the development of atherosclerosis in apoE-deficient mice. CD44-deficiency had no effect on plasma cholesterol levels but the extent of atherosclerosis in apoE-/-.C0444-/- mice was markedly reduced compared to apoE4-.CD44+I. littermates. The goal of the proposed studies is to determine the molecular and cellular mechanisms by which CD44 promotes atherogenesis. The following are the specific aims: 1. Define the role of CD44 in promoting atherosclerosis. The role of CD44 at different stages of development of atherosclerotic lesions will be determined in apoE-/-.CD44-/- mice of different ages and by treatment with anti-CD44 antibodies. The impact of CD44 deficiency on atherosclerosis in LDLRI- mice will be determined. We will assess functional activation of CD44 and determine the molecular form of CD44 involved in promoting atherogenesis. 2. Determine the relative effects of CD44 expression on bone marrow-derived hematopoietic cells versus vascular cells on atherogenesis and define the role of soluble CD44 in atherogenesis. We will determine if CD44 on hematopoietic cells alone or on non-hematopoietic cells alone in bone marrow chimeras promotes atherogenesis. Transgenic mice expressing CD44 on endothelial cells and vascular smooth muscle cells on the background of CD44 deficiency will be created and atherosclerosis analyzed. The contribution of soluble CD44 to atherogenesis will be determined. 3. Determine the cellular and molecular mechanisms by which CD44/HA interactions promote atherogenesis. We will test the hypotheses that: a)CD44/HA interactions promote leukocyte homing to sites of atherosclerotic lesions; b) CD44 and HA mediate macrophage-smooth muscle cell interactions; c) CD44 acts to organize hyaluronan-rich pericellular matrix; and d) CD44 deficiency impacts on the vascular gene expression profile using microarray technology. Since CD44 plays an important role in inflammation but is not required for normal leukocyte circulation, it is particularly attractive as a potential target for novel therapeutic interventions in atherosclerosis.
