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MRNAs expression profiles of high glucose-induced memory in human umbilical vein endothelial cells.

ABSTRACT: Purpose:A long-term "memory" of hyperglycemic stress, even when glycemia is normalized, has been previously reported in endothelial cells. However, the molecular mechanism of "metabolic memory" (MM) remains unknown. In this report, we sought to screen at the whole transcriptome level the genes that participate in MM. Methods:In the present research, RNA sequencing was used to determine the protein-coding mRNA expression profiles of human umbilical vein endothelial cells (HUVECs) under normal-glucose concentration (LG), high-glucose concentration (HG), and MM. A series of bioinformatic analyses was performed. HG-induced MM-involved up-regulated genes (up-HGMMGs) and HG-induced MM-involved down-regulated genes (down-HGMMGs) were identified. Afterward, based on up-HGMMGs and down-HGMMGs, the biological functions and signaling pathways were analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). In addition, several of the identified genes were validated by RT-qPCR. Results:A total of 726 HGMMGs were identified, including 210 down- and 516 up-HGMMGs, which were enriched in the cell cycle (hsa04110), oocyte meiosis (hsa04114), p53 signaling pathway (hsa04115), and oxidative phosphorylation (hsa00190), among others. The protein-protein-interaction (PPI) network consisted of 462 nodes and 2656 connections, and four main modules were identified by MCODE. The cell cycle (hsa04110), oocyte meiosis (hsa04114), p53 signaling pathway (hsa04115), and oxidative phosphorylation (hsa00190), among others, could be potential therapeutic targets of HG-induced MM in endothelial cells. The real-time PCR results validated the RNA-seq data. Conclusion:This study identified crucial mRNAs related to MM-persistent injury in endothelial cells even after switching the cells from high- glucose to normal glucose levels. Further research focusing on these mRNA may unravel new ways to modify MM in diabetes.

SUBMITTER: Jin G

PROVIDER: S-EPMC6662530 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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mRNAs expression profiles of high glucose-induced memory in human umbilical vein endothelial cells.

Jin Guoxi G Wang Qiong Q Pei Xiaoyan X Li Xiaoli X Hu Xiaolei X Xu Erqin E Li Minglong M

Diabetes, metabolic syndrome and obesity : targets and therapy 20190723

<h4>Purpose</h4>A long-term "memory" of hyperglycemic stress, even when glycemia is normalized, has been previously reported in endothelial cells. However, the molecular mechanism of "metabolic memory" (MM) remains unknown. In this report, we sought to screen at the whole transcriptome level the genes that participate in MM.<h4>Methods</h4>In the present research, RNA sequencing was used to determine the protein-coding mRNA expression profiles of human umbilical vein endothelial cells (HUVECs) u ...[more]

PMID: 31413614

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Project description:4-Hexylresorcinol (4HR) is used as a food preservative and an ingredient of toothpaste and cosmetics. The present study was performed using 233 antisera to determine the changes in protein expression induced by 4HR in human umbilical cord vein endothelial cells (HUVECs), and evaluated the 4HR-induced effects in comparison with previous results (Kim et al., 2019). Similar to RAW 264.7 cells, 4HR-treated HUVECs showed decreases in the expression of the proliferation-related proteins, cMyc/MAX/MAD network proteins, p53/RB and Wnt/β-catenin signaling, and they showed inactivation of DNA transcription and protein translation compared to the untreated controls. 4HR upregulated growth factors (TGF-β1, β2, β3, SMAD2/3, SMAD4, HGF-α, Met, IGF-1) and RAS signaling proteins (RAF-B, p38, p-p38, p-ERK-1, and Rab-1), and induced stronger expression of the cellular protection-, survival-, and differentiation-related proteins in HUVECs than in RAW 264.7 cells. 4HR suppressed NFkB signaling in a manner that suggests potential anti-inflammatory and wound healing effects by reducing M1 macrophage polarization and increasing M2 macrophage polarization in both cells. 4HR-treated HUVECs tended to increase the ER stress mediators by upregulating eIF2AK3, ATF4, ATF6, lysozyme, and LC3 and downregulating eIF2α and GADD153 (CHOP), resulting in PARP-1/AIF-mediated apoptosis. These results indicate that 4HR has similar effects on the protein expression of HUVECs and RAW 264.7 cells, but their protein expression levels differ according to cell types. The 4HR-treated cells showed global protein expression characteristic of anticancer and wound healing effects, which could be alleviated simultaneously by other proteins exerting opposite functions. These results suggest that although 4HR has similar effects on the global protein expression of HUVECs and RAW 264.7 cells, the 4HR-induced molecular interferences in those cells are complex enough to produce variable protein expression, leading different cell functions. Moreover, HUVECs have stronger wound healing potential to overcome the impact induced by 4HR than RAW 264.7 cells.

Project description:The increasing burden of diabetes in low and middle?income countries is attributable to both genetic and epigenetic factors. Environmental? and lifestyle?associated changes are also considered to be important contributors to this disease. The resultant co?morbidities arising from micro?and macrovascular changes in diabetes are difficult to manage and are an economic burden. However, very little is known about the molecular mechanisms that drive this phenotype. The present study aimed to investigate the role of sirtuin 1 (SIRT1)? and transcription box?3 (TBX?3)?mediated regulation of endothelial dysfunction, given the significance of SIRT1 in glucose metabolism and the role of TBX?3 in the maintenance of cellular proliferation, senescence and apoptosis. Following the recruitment of adult patients with and without diabetes, both SIRT1 and TBX?3 expression was confirmed to be present in the sera of the patients with diabetes and the patients without diabetes; however, both SIRT1 and TBX?3 expression levels were higher in the sera of the patients with diabetes. Human umbilical vein endothelial cells (HUVECs) were further used for in vitro studies. Using TBX?3 and SIRT1 knockdown models, the cellular responses to proliferation, migration, invasion and tube formation were investigated using an MTS, cell cycle analysis, wound healing, Transwell and tube formation assay, respectively. Western blotting was also used to determine the downstream signaling pathways involved. The genetic knockdown of TBX?3 in hyperglycemic conditions significantly decreased the cellular proliferation, migration, invasion and angiogenesis of HUVECs. It was subsequently identified that TBX?3 mediated its effects through the activation of AKT and vascular endothelial growth factor (VEGF) signaling. However, the genetic knockdown of SIRT1 in the presence of TBX?3 overexpression and glucose failed to activate the AKT and VEGF signaling pathways. In conclusion, the results of the present study suggested that SIRT1 may positively regulate TBX?3 in endothelial cells, therefore, SIRT1 and/or TBX?3 may serve as potential novel biomarkers for disease progression.

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MRNAs expression profiles of high glucose-induced memory in human umbilical vein endothelial cells.

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mRNAs expression profiles of high glucose-induced memory in human umbilical vein endothelial cells.

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