Impairment of endothelial MerTK accelerates atherosclerosis development
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Objective
Atherosclerosis is a chronic inflammatory disease primarily affecting large arteries and is the leading cause of cardiovascular disease. MER proto-oncogene tyrosine kinase (MerTK) plays a key role in regulating efferocytosis, a process for the clearance of apoptotic cells. This study investigates the specific contribution of endothelial MerTK to atherosclerosis development.
Approach and Results
Big data analytics, human microarray analyses, proteomics, and a unique mouse model with MerTK deficiency in endothelial cells ( MerTK flox/flox Tie2 Cre ) were utilized to elucidate the role of endothelial MerTK in atherosclerosis development. Our big data analytics, encompassing approximately 98881 cross analyses including 234 analyses for atherosclerosis in the aortic arch, along with human microarray data, reveal that inflammatory responses play a predominant role in atherosclerosis. In vivo, MerTK flox/flox Tie2 Cre mice and the littermate control MerTK flox/flox mice were used to establish an early stage of atherosclerosis model through a high-fat diet combined with AAV8-PCSK9 treatment. Consistent with big data analytics and human microarray analyses, our proteomics data showed that MerTK flox/flox Tie2 Cre mice demonstrated significantly enhanced proinflammatory signaling, mitochondrial dysfunction, and activated mitogen-activated protein kinase (MAPK) pathway compared to that of MerTK flox/flox mice. Endothelial MerTK deficiency induces endothelial dysfunction (enhanced endothelial inflammation, mitochondrial dysfunction, and activation of NADPH oxidases and MAPK signaling pathways) and subsequently causes smooth muscle cell (SMC) phenotypic alterations, ultimately promoting atherosclerosis development.
Conclusions
Our findings provide strong evidence that endothelial MerTK impairment serves as a novel mechanism in promoting atherosclerosis development.
