DOCK2 promotes atherosclerosis by mediating the endothelial cell inflammatory response

This study aims to explore the role of dedicator of cytokinesis 2 (DOCK2) in the pathogenesis of atherosclerosis. Low-density lipoprotein receptor (LDLR)-deficient mice with DOCK2 deficiency (LDLR-/-DOCK2-/-) and control (LDLR-/-) mice were fed with a high-fat diet (HFD) to induce atherosclerosis. The aortas and aortic roots were collected for atherosclerosis analysis. DOCK2 expression was induced in atherosclerotic lesions with increased expression of ICAM-1 and VCAM-1 after HFD for 4 weeks in LDLR-/- mice. LDLR-/-DOCK2-/- mice exhibited significantly decreased Oil-Red O (ORO) staining in both aortic roots and aortas compared to those in LDLR-/- mice after HFD for 12 weeks. Further, DOCK2 was highly expressed in ECs in atherosclerotic lesions of LDLR-/- mice and human patients. DOCK2 deficiency attenuated the induction of ICAM-1, VCAM-1, and MCP-1 in the aortic roots of mice fed HFD. In vitro data show that DOCK2 is required in TNF-α-induced expression of ICAM-1/VCAM-1/MCP-1 in human vascular ECs. DOCK2 knockdown attenuated the NF-κB phosphorylation induced by TNF-α, partially accounting for DOCK2 mediated vascular inflammation. In addition, DOCK2 knockdown inhibited TNF-α-induced VCAM-1 promoter activity in human vascular ECs. This study demonstrates that DOCK2 is a novel factor promoting the pathogenesis of atherosclerosis by modulating vascular EC inflammation.PMID:37838011 | DOI:10.1016/j.ajpath.2023.09.015
Source: Am J Pathol - Category: Pathology Authors: Source Type: research