Endothelial MerTK impairment promotes cardiac dysfunction in the condition of high fat diet

Cardiac fibrosis formation leads to cardiac dysfunction that is mainly caused by a high fat diet accompanied by an increased accumulation of apoptotic cells. MER proto-oncogene tyrosine kinase (MerTK) is a major receptor for efferocytosis, a process for the efficient clearance of apoptotic cells. This study was designed to investigate the novel role of endothelial MerTK in regulating cardiac dysfunction in the condition of high fat diet. MerTK deficiency in endothelial cells ( MerTK flox/flox Tie2 Cre ) mice and the littermates of MerTK flox/flox mice were injected with a single dose of AAV8-PCSK9 particles, followed by a high fat diet for two months. Multi-omics approach includes big data analytics and proteomics as well as single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) with human specimens. Immunostaining validation in vivo were also utilized to elucidate the underlying mechanisms of endothelial MerTK in cardiac dysfunction. The proteomics data showed that mitochondrial dysfunction, increased apoptosis and necrosis, defective phagosome formation, and impaired engulfment of cells represent the main signaling pathways involved in endothelial MerTK-mediated cardiac dysfunction. The immunostaining data indicates that endothelial MerTK deficiency promotes NADPH oxidases activation, cardiac fibrosis formation, phenotypic switching in smooth muscle cells (SMCs) and pro-inflammation response, while inhibiting expression of Apolipoprotein E (ApoE), all are key drivers to accelerate cardiac dysfunction. The scRNA-seq analysis in mouse hearts highlights the importance of endothelial functions in cardiac hypertrophy. The snRNA-seq analysis reveals endothelial MerTK dynamics in cardiac dysfunction based on specimens from human patients with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). These findings provide compelling evidence that endothelial MerTK impairment is a novel mechanism in promoting cardiac dysfunction. • The role of endothelial MerTK in cardiac function remains unknown. • Multi-omics were performed to cross-validate the role of endothelial MerTK in cardiac dysfunction. • Endothelial MerTK deficiency promotes cardiac fibrosis, SMC phenotypic alterations and inflammation response. • SnRNA-seq reveals endothelial dynamics in human DCM and HCM.