Abstract 14929: Dedicator of Cytokinesis 2 Promotes Atherosclerosis Through Mediating Vascular Inflammation

Atherosclerosis is a leading cause of sudden death in patients with cardiovascular disease. It is the major risk factor of coronary artery disease and stroke. The pathophysiological mechanisms of atherosclerosis are complex and there is lack of effective pharmacotherapy for treating atherosclerosis. Dedicator of cytokinesis 2 (DOCK2) plays important roles in immune functions and inflammatory processes. This study aims to explore the role of DOCK2 in the development of atherosclerosis. We generated double knockout (DOCK2-/-;LDLR-/-) mice. The LDLR-/- and DOCK2-/-;LDLR-/- male mice were fed high-fat diet (HFD) for 4 weeks and/or 12 weeks followed by the collection of the aorta and aortic roots. IHC staining showed that DOCK2 was induced in atherosclerotic lesions with increased expression of ICAM-1, VCAM-1, and MCP-1 after HFD for 4 weeks in LDL-/- mice. DOCK2-/-;LDLR-/- mice exhibited a significantly decreased lesion formation compared to LDLR-/- mice after HFD for 12 weeks as shown by Oil-Red O (ORO) staining of the aorta. ORO staining of aortic roots confirmed the reduced lesion size in DOCK2-/-;LDLR-/- mice. DOCK2 deficiency also attenuated the induction of ICAM-1, VCAM-1, and MCP-1 expression by HFD for 12 weeks. These data indicate that DOCK2 is essential for the lesion formation by inducing the adhesion and invasion related molecule expression. Macrophages have been reported to contribute to atherogenesis. Therefore, we evaluated macrophage infiltration in aortic roots of LDLR-/- and DOCK2-/-;LDLR-/- mice fed with HFD for 12 weeks. The data show that there was significantly attenuated macrophage infiltration in aortic roots of DOCK2-/-;LDLR-/- mice compared with that in LDLR-/- mice, as shown by the decreased F4/80-positive cells. Together, our data demonstrate that DOCK2 deficiency attenuates atherosclerosis by alleviating vascular inflammation.