Atherosclerosis, the major common risk factor of coronary artery disease and stroke, is the primary cause of death particularly in the developed world. The pathophysiological mechanisms of atherosclerosis are quite complex, and the inflammatory responses of vascular endothelial cells (ECs), the adhesion and infiltration of monocytes, and the oxidized LDL (ox-LDL)-induced transformation of macrophages (M?) into foam cells are vital events in this process. However, molecular mechanisms underlying the EC inflammation, the monocyte adhesion to ECs, and the activation/function of M? especially factors regulating these processes in atherosclerosis remain largely unknown. Our exciting preliminary data strongly support that dedicator of cytokinesis 2 (DOCK2) is a novel regulator for EC inflammation/monocyte adhesion/M? activation/function in atherogenesis. DOCK2 is essential for ox-LDL- or TNF-?-induced expression of pro-inflammatory cytokines and adhesion molecules like IL-6, MCP-1, ICAM-1, and VCAM-1 in ECs, suggesting that DOCK2 mediates the EC inflammation. In addition, DOCK2 deficiency (DOCK2-/-) inhibits TNF-?-induced human monocyte adhesion to ECs and blocks M? activation/function. Moreover, DOCK2-/- decreases macrophage phagocytosis through the suppression of scavenger receptor A (SR-A) and SR-B (CD36). In vivo, DOCK2 is induced in both mouse and human atherosclerotic lesion ECs and other cells. DOCK2-/- in mice significantly attenuates the lesion size, M? infiltration, and the expression of adhesion molecules and pro-inflammatory cytokines including NF-?B, the most common regulator of inflammation in atherosclerosis. These findings strongly support a novel hypothesis that DOCK2 promotes the development of atherosclerosis through mediating EC inflammation, monocyte adhesion to ECs as well as M? function, which will be tested by three Specific Aims.
In Aim 1 we will establish the role of DOCK2 in atherosclerosis formation in vivo by examining the modulation of EC inflammation/phenotype.
In Aim 2 we will test whether DOCK2 mediates monocyte adhesion to ECs by regulating endothelial inflammation and adhesion molecule expression; and in Aim 3 we will determine if DOCK2 regulates the development of atherosclerosis through mediating M? activation/function. Completion of the proposed studies will establish the pivotal role of DOCK2 and the underlying novel mechanisms controlling the development and progression of atherosclerosis, which may ultimately contribute to the development of novel therapeutics for treating atherosclerosis.
Atherosclerosis is the primary cause of heart attack, stroke, and peripheral arterial disease, which accounts for ~40% of all deaths in the United States. We have identified a gene called dedicator of cytokinesis 2, which plays a key role in endothelial inflammation and macrophage activation/function in atherogenesis. The proposed studies will shed new lights on the pathogenesis of atherosclerosis and may ultimately lead to the identification of novel targets for developing therapeutic agent to treat atherosclerosis.
