DOCK2 Promotes Atherosclerosis by Mediating the Endothelial Cell Inflammatory Response

Area of Science:

• Cardiovascular Biology
• Immunology
• Cellular and Molecular Medicine

Background:

• Atherosclerosis, a major cause of cardiovascular disease mortality, involves inflammatory changes in vascular endothelial cells.
• The role of dedicator of cytokinesis (DOCK)-2 protein in the pathogenesis of atherosclerosis remains largely unexplored.

Purpose of the Study:

• To investigate the role of DOCK2 protein in the development and progression of atherosclerosis.
• To elucidate the molecular mechanisms by which DOCK2 influences vascular inflammation in atherosclerosis.

Main Methods:

• Utilized low-density lipoprotein receptor knockout (Ldlr-/-) and Ldlr-/-Dock2-/- mice fed a high-fat diet to model atherosclerosis.
• Assessed atherosclerotic lesion size using Oil Red O staining in aortic roots and aortas.
• Quantified inflammatory markers (ICAM-1, VCAM-1, MCP-1) and analyzed NF-κB signaling pathway activation in mouse tissues and human vascular endothelial cells (ECs) in vitro.

Main Results:

• DOCK2 expression was upregulated in atherosclerotic lesions of control mice after high-fat diet.
• Ldlr-/-Dock2-/- mice showed significantly reduced atherosclerotic burden compared to controls.
• DOCK2 deficiency attenuated inflammatory markers (ICAM-1, VCAM-1, MCP-1) and NF-κB activation in response to TNF-α stimulation in both mouse models and human ECs.

Conclusions:

• DOCK2 plays a critical role in promoting atherosclerosis by enhancing vascular endothelial cell inflammation.
• DOCK2 modulates the expression of key adhesion molecules and chemokines involved in the inflammatory process.
• Targeting DOCK2 may represent a novel therapeutic strategy for mitigating atherosclerosis and cardiovascular disease.