Metformin Modulates High Glucose-Incubated Human Umbilical Vein Endothelial Cells Proliferation and Apoptosis Through AMPK/CREB/BDNF Pathway

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.

<p>Hydrogen Sulfide Protects Against High Glucose-Induced Human Umbilical Vein Endothelial Cell Injury Through Activating PI3K/Akt/eNOS Pathway</p>

“…Although it is well known that HG plays a key role in diabetic endothelial dysfunction and atherosclerosis, the mechanisms responsible for HG-induced endothelial damage remain to be elucidated. The HG (33 mM)-induced HUVECs injury model was employed to investigate the underlying mechanisms of endothelial injury, and further investigated cytoprotection of H 2 S. In the present study, HG treatment for 24 hrs caused a significant reduction in the cell viability of HUVECs, which was consistent with the results from Han et al, 34 However, several studies demonstrated that the inhibitory effects of HG on HUVEC viability were observed after 48-hr 35 and 72-hr treatment. [36][37][38][39] The inconsistency regarding the HG treatment duration across different studies may be due to the different culture conditions, different sources for obtaining HUVECs, or different experimental protocols, which may require further examination.…”

Metformin inhibits high glucose-induced smooth muscle cell proliferation and migration

“…This may be due to the inhibition of the inflammatory response and vascular calcification in VSMC by metformin [24,25]. Metformin also inhibits proliferation of tumor and endothelial cells [26,27]. In our study, metformin decreased VSMC proliferation in the high-glucose condition.…”

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

“…MET exerted protective effect against hyperglycemia-induced endothelial impairment, which was contributed to MET improving HG-inhibited GLI1 activity and BNIP3 expression in HUVECs ( Niu et al., 2019 ). MET was also reported to promote angiogenic potential of HUVECs probably by the regulation of endocan dynamics under high glucose condition ( Zolali et al., 2019 ) and modulate high glucose-induced HUVECs proliferation and apoptosis through AMPK/CREB/BDNF Pathway ( Han et al., 2018 ). However, our study focused on exploring the mechanism of MET in modulating hyperglycemic-induced oxidative stress in order to open a new perspective of MET in the treatment of GDM (HG).…”