Abstract Tu017: MerTK inhibition aggravates partial carotid ligation-induced atherosclerosis

Abstract

Introduction: Partial carotid ligation (PCL) is a widely used model to generate acute disturbed flow (d-flow) in left carotid artery (LCA), leading to rapid endothelial dysfunction and atherosclerosis formation. While the right carotid artery (RCA) without PCL is a built-in control characterized by steady flow (s-flow). Endothelial cells (ECs) form a single cell layer that is constantly exposed to blood flow patterns and play important roles in atherosclerosis. MER proto-oncogene tyrosine kinase (MerTK) is the major receptor for efferocytosis, a process of the efficient clearance of apoptotic cells. MerTK is mainly expressed in macrophages and there are very limited reports focusing on MerTK function in ECs. This study was designed to investigate the role of blood flow patterns in regulating MerTK expression in aortic ECs and its contributions to the development of atherosclerosis. Methods: Partial carotid artery ligation combined with AAV-PCSK9 and high fat diet (HFD) were used to set up acute atherosclerosis within 4 weeks with WT and MerTK -/- mice. Proteomics and molecular experiments were applied to reveal the potential mechanism pathways. Results: Our proteomics data showed that, compared with WT group, MerTK -/- aggravates atherosclerosis in LCA through upregulation of endothelial dysfunction markers (e.g. IL-1β, NF-κB, TLR4, MAPK signaling) and mitochondrial dysfunction. Our immunostaining data further validates the proteomics data, showing that MerTK -/- induces impaired endothelial efferocytosis and expression of endothelial dysfunction markers (e.g., Caspase-3, NF-κB, TLR4, vWF, VCAM-1, and P22 phox ) and promotes the development of atherosclerosis. Conclusion: Our data suggests that endothelial MerTK is sensitive to d-flow and determines endothelial efferocytosis in vivo. MerTK inhibition promotes endothelial dysfunction and atherosclerosis. Our data may provide novel evidence and reference opinions for the application of endothelial MerTK- targeted therapeutics to treat atherosclerosis.