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, and M¿
activation/function in atherogenesis. DOCK2 is essential for ox-LDL- or TNF-a-induced expression of proinflammatory
cytokines and adhesion molecules such as IL-6, MCP-1, ICAM-1, and VCAM-1 in ECs,
suggesting that DOCK2 mediates EC inflammation. In addition, DOCK2 deficiency (DOCK2-/-) inhibits TNF-a-
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 proinflammatory
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.