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.
Highlights
The public health system in China is increasingly burdened by a disproportionate increase in type 1 and type 2 diabetes (T2D) [1]
Western blotting results revealed that transcription box‐3 (TBX‐3) protein expression levels were significantly increased by glucose in Human umbilical vein endothelial cells (HUVECs) in a dose‐dependent manner compared with the control group (P
HUVECs were treated with 30 mM glucose for different time points (0, 12, 24, 36 or 48 h); the western blotting results revealed that TBX‐3 expression levels were increased by glucose in a time‐dependent manner (P
Summary
The public health system in China is increasingly burdened by a disproportionate increase in type 1 and type 2 diabetes (T2D) [1]. While the mortality rate of the diseases and their presentation differ significantly, the overall morbidity and associated mortality rates associated with both the diseases are increasing sharply [2]; for example, the morbidity rate in the elderly population with type 2 diabetes was recorded as 21.4 and 24.8% in 2001 and 2010, respectively, in China [2,3]. A multitude of factors, such as obesity, age, diet, physical activity, and genetic and epigenetic modifications have been identified to be responsible for the increasing disease burden in the Chinese population [4]. Region‐specific studies of diabetes have reported an incidence rate of 1.01 per 100,000 person years across all age groups in China [5], with an increased incidence rate in males compared with females [6]. It has been hypothesized that microvasculopathy may give rise to macrovasculopathy through hypoxia and changes in the vasa vasorum [10]; the changes in the vasa vasorum have been often associated with endothelial dysfunction [11]; the molecular mechanisms driving endothelial cell plasticity under hyperglycemic stress have received little attention
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