Abstract
Cardiovascular disease (CVD) is a leading cause of mortality and morbidity among patients with diabetes. Endothelial dysfunction is an early physiological event in CVD. Metformin, a common oral antihyperglycemic agent, has been demonstrated to directly affect endothelial cell function. Brain-derived neurotrophic factor (BDNF), originally discovered in the brain as a neurotrophin, has also been reported to play a protective role in the cardiovascular system. In our study, we demonstrated that high glucose (HG) reduced cell proliferation and induced cell apoptosis via changes in BDNF expression and that metformin reversed the effects of HG injury by upregulating BDNF expression. Furthermore, we found that cyclic AMP response element binding (CREB) phosphorylation was reduced in HG-treated human umbilical vein endothelial cells (HUVECs), and this effect was reversed by the metformin treatment. However, the metformin effect on BDNF levels in HG-incubated HUVECs was blocked by a CREB inhibitor, which indicated that BDNF expression is regulated by metformin through CREB activation. In addition, we found that adenosine monophosphate-activated protein kinase (AMPK) activation is involved in CREB/BDNF regulation in HG-incubated HUVECs treated with metformin and that an AMPK inhibitor impaired the protective effects of metformin on HG-treated HUVECs. In conclusion, this study demonstrated that metformin affects cell proliferation and apoptosis via the AMPK/CREB/BDNF pathway in HG-incubated HUVECs.
Highlights
The prevalence of diabetes mellitus, type 2 diabetes mellitus (T2DM), has increased dramatically in recent years, and the number of 20- to 79-year-old patients with diabetes is predicted to increase to 642 million by 2040 (Ogurtsova et al, 2017)
Previous studies have demonstrated that HG caused endothelial cell dysfunction (Sheu et al, 2005), so we applied a Cell Counting Kit-8 (CCK8) assay and a bromo-2 -deoxyuridine (BrdU) incorporation assay to determine the effects of HG on cell viability and proliferation
It was determined that there were more transferase-mediated dUTP nick-end labeling (TUNEL)+ human umbilical vein endothelial cells (HUVECs) in the HG-treated group than in the control group (Figure 1D). These results demonstrated that HG reduced cell proliferation and induced cell apoptosis
Summary
The prevalence of diabetes mellitus, type 2 diabetes mellitus (T2DM), has increased dramatically in recent years, and the number of 20- to 79-year-old patients with diabetes is predicted to increase to 642 million by 2040 (Ogurtsova et al, 2017). Cardiovascular disease (CVD) is a leading cause of mortality and morbidity among patients with diabetes. 75% of patients with T2DM will die of CVD (Mancini et al, 2017). Studies have indicated that diabetes or highglucose (HG) levels trigger multiple endothelial dysfunctions, such as dysregulated endothelial cell proliferation, migration, and apoptosis (Baumgartner-Parzer et al, 1995; Tousoulis et al, 2013; Dong et al, 2017). Endothelial dysfunction is an early physiological event in CVD (Vanhoutte, 2009)
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