BMP4, Inflammation and Atherosclerosis

动脉粥样硬化优先发生在分支动脉或弯曲动脉在不稳定剪切条件下易发生病变的区域，而单向层流剪切（LS）下的动脉区域相对无病变。目前，人们普遍认为动脉粥样硬化是一种炎症性疾病，动脉粥样硬化早期阶段的特征是病变易发区域粘附分子的表达和随后单核细胞的募集。此外，振荡剪切（OS）等不稳定剪切条件会诱导活性氧（ROS）的产生和炎症反应。尽管付出了巨大的努力，但不稳定剪切条件诱导炎症和动脉粥样硬化的确切机制尚不清楚。在这项应用中，我们提出了一种新的机制，即OS通过调节ros依赖的方式促进炎症反应和动脉粥样硬化

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.