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Transcription box?3 protects human umbilical vein endothelial cells in a high?glucose environment through sirtuin 1/AKT signaling.

ABSTRACT: 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.

SUBMITTER: Yu Z

PROVIDER: S-EPMC7339771 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Transcription box‑3 protects human umbilical vein endothelial cells in a high‑glucose environment through sirtuin 1/AKT signaling.

Yu Zhanjiang Z Zhang Wei W Zhang Xiankun X Xu Donghui D Wang Na N

Molecular medicine reports 20200615 2

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 investig ...[more]

PMID: 32627000

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Project description:BackgroundThe balance between endothelial cell survival and apoptosis during stress is an important cellular process for vessel integrity and vascular homeostasis, and it is also pivotal in angiogenesis during the development of many vascular diseases. However, the underlying molecular mechanisms remain largely unknown. Although both transcription and alternative splicing are important in regulating gene expression in endothelial cells under stress, the regulatory mechanisms underlying this state and their interactions have not yet been studied on a genome-wide basis.ResultsHuman umbilical vein endothelial cells (HUVECs) were treated with cobalt chloride (CoCl2) both to mimic hypoxia and to induce cell apoptosis and alternative splicing responses. Cell apoptosis rate analysis indicated that HUVECs exposed to 300 microM CoCl2 for 24 hrs were initially counterbalancing apoptosis with cell survival. We therefore used the Affymetrix exon array system to determine genome-wide transcript- and exon-level differential expression. Other than 1583 differentially expressed transcripts, 342 alternatively spliced exons were detected and classified by different splicing types. Sixteen alternatively spliced exons were validated by RT-PCR. Furthermore, direct evidence for the ongoing balance between HUVEC survival and apoptosis was provided by Gene Ontology (GO) and protein function, as well as protein domain and pathway enrichment analyses of the differentially expressed transcripts. Importantly, a novel molecular module, in which the heat shock protein (HSP) families play a significant role, was found to be activated under mimicked hypoxia conditions. In addition, 46% of the transcripts containing stress-modulated exons were differentially expressed, indicating the possibility of combinatorial regulation of transcription and splicing.ConclusionThe exon array system effectively profiles gene expression and splicing on the genome-wide scale. Based on this approach, our data suggest that transcription and splicing not only regulate gene expression, but also carry out combinational regulation of the balance between survival and apoptosis of HUVECs under mimicked hypoxia conditions. Since cell survival following the apoptotic challenge is pivotal in angiogenesis during the development of many vascular diseases, our results may advance the knowledge of multilevel gene regulation in endothelial cells under physiological and pathological conditions.

Dataset Information

Transcription box?3 protects human umbilical vein endothelial cells in a high?glucose environment through sirtuin 1/AKT signaling.

Publications

Transcription box‑3 protects human umbilical vein endothelial cells in a high‑glucose environment through sirtuin 1/AKT signaling.

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