Endothelial MerTK impairment accelerates the development of atherosclerosis

Area of Science:

• Cardiovascular Biology
• Inflammation Research
• Molecular Mechanisms of Disease

Background:

• Atherosclerosis is a major cause of cardiovascular disease, characterized by chronic arterial inflammation.
• MER proto-oncogene tyrosine kinase (MerTK) is crucial for efferocytosis, the clearance of apoptotic cells.
• The specific role of endothelial MerTK in atherosclerosis remains to be fully elucidated.

Purpose of the Study:

• To investigate the contribution of endothelial MerTK to the development of atherosclerosis.
• To elucidate the molecular mechanisms by which endothelial MerTK influences atherosclerosis progression.

Main Methods:

• Utilized big data analytics, human microarray data, and proteomics.
• Employed a unique mouse model with endothelial cell-specific MerTK deficiency (MerTK^flox/floxTie2^Cre).
• Established an early-stage atherosclerosis model using a high-fat diet and AAV8-PCSK9 treatment.

Main Results:

• Big data and human microarray analyses confirmed the predominant role of inflammation in atherosclerosis.
• Endothelial MerTK deficiency in mice led to enhanced proinflammatory signaling, mitochondrial dysfunction, and MAPK pathway activation.
• Endothelial dysfunction, smooth muscle cell alterations, and ultimately atherosclerosis development were promoted by MerTK deficiency.

Conclusions:

• Endothelial MerTK deficiency significantly exacerbates atherosclerosis development.
• Impairment of endothelial MerTK represents a novel mechanism promoting atherosclerosis.
• The miR-218-5p/EC^MerTK/MAPK axis is implicated in endothelial MerTK-mediated atherosclerosis.