Disturbed flow impairs MerTK-mediated efferocytosis in aortic endothelial cells during atherosclerosis
Jinzi Wu1, Shijie Liu1, Oishani Banerjee1
1Department of Biology, Georgia State University, Atlanta, GA, 30303, USA.
Abstract:
Background: MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for efferocytosis, a process for the clearance of apoptotic cells. MerTK is mainly expressed in macrophages and immature dendritic cells. There are very limited reports focused on MerTK biology in aortic endothelial cells (ECs). It remains unclear for the role of blood flow patterns in regulating MerTK-mediated efferocytosis in aortic ECs. This study was designed to investigate whether endothelial MerTK and EC efferocytosis respond to blood flow patterns during atherosclerosis. Methods: Big data analytics, RNA-seq and proteomics combined with our in vitro and in vivo studies were applied to reveal the potential molecular mechanisms. Partial carotid artery ligation combined with AAV-PCSK9 and high fat diet were used to set up acute atherosclerosis in 4 weeks. Results: Our data showed that MerTK is sensitive to blood flow patterns and is inhibited by disturbed flow and oscillatory shear stress in primary human aortic ECs (HAECs). The RNA-seq data in HAECs incubated with apoptotic cells showed that d-flow promotes pro-inflammatory pathway and senescence pathway. Our in vivo data of proteomics and immunostaining showed that, compared with WT group, MerTK-/- aggravates atherosclerosis in d-flow areas through upregulation of endothelial dysfunction markers (e.g. IL-1β, NF-κB, TLR4, MAPK signaling, vWF, VCAM-1 and p22phox) and mitochondrial dysfunction. Interestingly, MerTK-/-induces obvious abnormal endothelial thickening accompanied with decreased endothelial efferocytosis, promoting the development of atherosclerosis. Conclusions: Our data suggests that blood flow patterns play an important role in regulating MerTK-mediated efferocytosis in aortic ECs, revealing a new promising therapeutic strategy with EC efferocytosis restoration to against atherosclerosis.
Insights
Blood flow patterns regulate MER proto-oncogene tyrosine kinase (MerTK) in aortic endothelial cells, impacting efferocytosis and atherosclerosis development. Restoring endothelial cell efferocytosis offers a potential therapeutic strategy.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cell Biology
Background:
- MER proto-oncogene tyrosine kinase (MerTK) is crucial for efferocytosis, primarily in immune cells.
- Limited research exists on MerTK in aortic endothelial cells (ECs) and its regulation by blood flow.
- The role of MerTK-mediated efferocytosis in ECs under varying flow conditions during atherosclerosis is largely unknown.
Purpose of the Study:
- To investigate the impact of blood flow patterns on endothelial MerTK expression and function.
- To determine if MerTK-mediated efferocytosis in aortic ECs is responsive to hemodynamic forces.
- To explore the molecular mechanisms linking disturbed flow, MerTK, and atherosclerosis.
Main Methods:
- Utilized big data analytics, RNA-seq, and proteomics.
- Employed in vitro studies with primary human aortic ECs (HAECs) and in vivo atherosclerosis models.
- Established acute atherosclerosis using carotid artery ligation, AAV-PCSK9, and high-fat diet in MerTK knockout mice.
Main Results:
- Disturbed blood flow and oscillatory shear stress inhibit MerTK in HAECs.
- Disturbed flow promotes pro-inflammatory and senescence pathways in HAECs.
- MerTK deficiency exacerbates atherosclerosis in disturbed flow regions, increasing endothelial dysfunction and mitochondrial dysfunction markers.
- MerTK deficiency leads to endothelial thickening and reduced efferocytosis, promoting atherosclerosis.
Conclusions:
- Blood flow patterns significantly regulate MerTK-mediated efferocytosis in aortic ECs.
- MerTK plays a protective role in aortic ECs against atherosclerosis by facilitating efferocytosis.
- Restoring endothelial cell efferocytosis presents a novel therapeutic avenue for combating atherosclerosis.
