Abstract
Tet methylcytosine dioxygenase 2 (TET2) mediates the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The loss of TET2 is associated with advanced atherosclerotic lesions. Our previous study showed that TET2 improves endothelial cell function by enhancing endothelial cell autophagy. Accordingly, this study determined the role of TET2 in atherosclerosis and potential mechanisms. In ApoE−/− mice fed high-fat diet, TET2 overexpression markedly decreased atherosclerotic lesions with uniformly increased level of 5hmC and decreased level of 5mC in genomic DNA. TET2 overexpression also promoted autophagy and downregulated inflammation factors, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, monocyte chemotactic protein 1, and interleukin-1. Consistently, TET2 knockdown with small hairpin RNA (shRNA) in ApoE−/− mice decreased 5hmC and increased 5mC levels in atherosclerotic lesions. Meanwhile, autophagy was inhibited and atherosclerotic lesions progressed with an unstable lesion phenotype characterized by large lipid core, macrophage accumulation, and upregulated inflammation factor expression. Experiments with the cultured endothelial cells revealed that oxidized low-density lipoprotein (ox-LDL) inhibited endothelial cell autophagy. TET2 shRNA strengthened impaired autophagy and autophagic flux in the ox-LDL-treated endothelial cells. TET2 overexpression reversed these effects by decreasing the methylation level of the Beclin 1 promoter, which contributed to the downregulation of inflammation factors. Overall, we identified that TET2 was downregulated during the pathogenesis of atherosclerosis. The downregulation of TET2 promotes the methylation of the Beclin 1 promoter, leading to endothelial cell autophagy, impaired autophagic flux, and inflammatory factor upregulation. Upregulation of TET2 may be a novel therapeutic strategy for treating atherosclerosis.
Highlights
Atherosclerosis, a complex disease that involves chronic inflammation and vascular remodeling processes, is the leading cause of death and morbidity among adults in developed countries
Results showed that the levels of TET2 and its product 5hmC decreased in atherosclerotic lesions
TET2 contributed to the promoter methylation status of Beclin 1, a key regulator of autophagy that governs the autophagic process by regulating the generation of phosphatidylinositol3phosphate and the subsequent recruitment of additional Atg proteins that orchestrate autophagosome formation [23]
Summary
Atherosclerosis, a complex disease that involves chronic inflammation and vascular remodeling processes, is the leading cause of death and morbidity among adults in developed countries. Increasing evidence has indicated that autophagy is impaired during atherosclerotic plaque development and contributes to lipid metabolism www.impactjournals.com/oncotarget dysfunction and vascular endothelial cell (EC) dysfunction [1,2,3]. Autophagy is a dynamic process of recycling in which cells degrade malfunctioning or damaged proteins and organelles within their lysosomes; this process plays a crucial role in cellular homeostasis. DNA methylation of some key autophagy-related (ATG) genes regulates autophagy. LC3I, an important positive regulator of autophagy, is frequently methylated in esophageal squamous-cell carcinoma [4]. Autophagy-related protein Beclin 1 promoter displays aberrant methylation, and its expression is significantly downregulated in breast tumors [5]
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