Wenzhuo Cheng

The National Genomics Data Center (NGDC), which is a part of the China National Center for Bioinformation (CNCB), offers a comprehensive suite of database resources to support the global scientific community. Amidst the unprecedented accumulation of multi-omics data, CNCB-NGDC is committed to continually evolving and updating its core database resources through big data archiving, integrative analysis and value-added curation. Over the past year, CNCB-NGDC has expanded its collaborations with international databases and established new subcenters focusing on biodiversity, traditional Chinese medicine and tumor genetics. Substantial efforts have been made toward encompassing a broad spectrum of multi-omics data, developing innovative resources and enhancing existing resources. Notably, new resources have been developed for single-cell omics (scTWAS Atlas), genome and variation (VDGE), health and disease (CVD Atlas, CPMKG, Immunosenescence Inventory, HemAtlas, Cyclicpepedia, IDeAS), biodiversity and biosynthesis (RefMetaPlant, MASH-Ocean) and research tools (CCLHunter). All resources and services are publicly accessible at https://ngdc.cncb.ac.cn.

BackgroundAtherosclerosis (AS) is the basis of diabetic macrovascular complications. The plasma low-density lipoprotein (LDL) particles transcytosis across endothelial cells (ECs) and deposition under the endothelium is the initiation step of AS. We previously reported that high glucose inhibits the autophagic degradation of Caveolin-1 and promote LDL transcytosis across ECs, which in turn accelerates atherosclerotic progression. Since Sirt6 is a chromatin-associated protein with deacetylation activity, whether it can regulate Caveolin-1 acetylation and regulating the autophagic degradation of Caveolin-1 remains elusive.MethodsAutophagy and histone acetylation were assessed in the umbilical cords of patients with gestational diabetes mellitus (GDM) by immunohistochemistry. An in vitro model of LDL transcytosis was established, and the role of Sirt6 in LDL transcytosis across endothelial cells was clarified. The effect of Sirt6 on the autophagic degradation of Caveolin-1 under hyperglycemic conditions was explored in a streptozotocin (STZ)-induced diabetic AS model established using the ApoE−/− mice.ResultsCaveolin-1 and acetylated histone H3 levels were significantly increased, while LC3B and Sirt6 were downregulated in the monolayer of the vascular wall from GDM and type 2 diabetes mellitus (T2DM) patients. Immunoprecipitation assays showed that Sirt6 interacts with Caveolin-1 and specifically mediated its acetylation levels. Immuno-electron microscopy (EM) further indicated that Sirt6 overexpression triggered the autophagic lysosomal degradation of Caveolin-1. ECs-specific overexpression of Sirt6 by adeno-associated viral vector serotype 9 (AAV9) induced autophagy, reduced Caveolin-1 expression, and ameliorated atherosclerotic plaque formation in STZ-induced diabetic ApoE−/− mice.ConclusionSirt6-mediated acetylation of Caveolin-1 activates its autophagic degradation and inhibits high glucose-stimulated LDL transcytosis. Thus, the Sirt6/Caveolin-1 autophagic pathway plays a crucial role in diabetic AS, and the overexpression or activation of Sirt6 is a novel therapeutic strategy.

Abstract Objective To elucidate the mechanism whereby advanced glycation end products (AGEs) accelerate atherosclerosis (AS) and to explore novel therapeutic strategies for atherosclerotic cardiovascular disease. Methods and results The effect of AGEs on low-density lipoprotein (LDL) transcytosis across endothelial cells (ECs) was assessed using an in vitro model of LDL transcytosis. We observed that AGEs activated the receptor for advanced glycation end products (RAGE) on the surface of ECs and consequently upregulated Caveolin-1, which in turn increased caveolae-mediated LDL transcytosis and accelerated AS progression. Our molecular assessment revealed that AGEs activate the RAGE-NF-κB signaling, which then recruits the NF-κB subunit p65 to the RAGE promoter and consequently enhances RAGE transcription, thereby forming a positive feedback loop between the NF-κB signaling and RAGE expression. Increased NF-κB signaling ultimately upregulated Caveolin-1, promoting LDL transcytosis, and inhibition of RAGE suppressed AGE-induced LDL transcytosis. In ApoE −/− mice on a high-fat diet, atherosclerotic plaque formation was accelerated by AGEs but suppressed by EC-specific knockdown of RAGE. Conclusion AGEs accelerate the development of diabetes-related AS by increasing the LDL transcytosis in ECs through the activation of the RAGE/NF-κB/Caveolin-1 axis, which may be targeted to prevent or treat diabetic macrovascular complications.

Elevated plasma low density lipoprotein (LDL) is an established risk factor for cardiovascular disease. In addition to being able to cross the endothelial barrier to become accumulated in subendothelial space and thereby initiate atherosclerosis, LDL may exert a direct effect on vascular endothelial cells through activation of LDL receptor and its downstream signaling. Whether LDL can modulate the signaling for autophagy in endothelial cells is not clear. The present study firstly demonstrated that LDL can suppress endothelial autophagy through activation of the PI3K/Akt/mTOR signaling pathway and can promote glucose uptake by translocating glucose transporter 1 (GLUT1) from cytoplasm to cell membrane, actions similar to those of insulin. A co-immunoprecipitation assay found that LDL receptor (LDLR) and insulin receptor (IR) formed a complex in HUVECs. Knock down of the insulin receptor by small interfering RNA blocked the suppression of autophagy by LDL, as well as the signaling pathway involved. We conclude that LDL may mimic the action of insulin in endothelial cells, which might partly explain the increased incidence of diabetes in patients receiving some LDL-lowering therapy.