Atherosclerosis preferentially occurs in lesion-prone areas exposed to unstable shear stress conditions in branched or curved arteries, while the arterial regions exposed to unidirectional laminar shear (LS) are relatively lesion-free. It is now well accepted that atherosclerosis is an inflammatory disease and that the hallmarks of the earliest stages of atherogenesis are adhesion molecule expression and subsequent recruitment of monocytes in the lesion prone areas. In addition, unstable shear conditions such as oscillatory shear (OS) induce production of reactive oxygen species (ROS) and inflammatory responses. Despite intense efforts, the precise mechanisms by which unstable shear conditions induce inflammation and atherosclerosis are not clear. In this application, we propose a novel mechanism by which OS promotes inflammatory responses and atherosclerosis in a ROS-dependent manner via regulation of the expression of a unique vascular gene product, bone morphogenic protein-4 (BMP4). Our preliminary data show that BMP4 gene expression is dramatically increased in mouse aortic endothelial cells (MAEC) exposed to OS when compared to cells exposed to LS. Moreover, we found that BMP4 produced by OS induced surface expression of endothelial intercellular adhesion molecule-1 (ICAM-1) and subsequent monocyte adhesion. Based on these findings, we propose the central hypothesis that exposure of endothelial cells to OS induces BMP4 expression, which in tum initiates an inflammatory cascade in a ROS- and NFkappaB-dependent manner resulting in monocyte recruitment, foam cell formation, and subsequent atherosclerosis. In the first specific aim, we will determine the signaling pathways by which BMP4 induces expression of ICAM-1 and monocytes adhesion. The role of the NFkappanB, MAP kinases and SMAD proteins will be investigated. In the second aim, we plan to determine the role of ROS in BMP4-induced expression of ICAM-1 and monocyte adhesion, based on our preliminary results showing that antioxidants block these BMP4-induced inflammatory responses.
In aims 3 and 4, we will test these concepts in an animal model of atherosclerosis. Specifically in aim 3, we will determine the role of BMP4 in the macrophage recruitment and atherosclerosis in ApoE -/- mice, while aim 4 will center on determining the role of the BMP4 receptor (ALK) in macrophage recruitment and atherosclerosis in endothelial-targeted ALK-/-.ApoE-/- mice. The identification of BMP4 as an inflammatory cytokine will not only provide novel insight into the mechanisms underlying the focal development of atherosclerosis in lesion-prone areas, but also may identify novel diagnostic and therapeutic approaches in atherosclerosis.
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