Dataset Information

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

ABSTRACT: Gestational diabetes mellitus (GDM) causes oxidative stress in mothers and infants and causes vascular endothelial dysfunction, which is a key factor for maternal and fetal cardiovascular diseases in the later stage of GDM, seriously threatening the life and health of mothers and infants. Nowadays, metformin (MET) has been discovered to improve endothelial function, but studies regarding the mechanism of MET improving endothelial cell function and alleviating endothelial function under hyperglycemia are still extremely limited. We aimed to investigate whether MET exerts its protective role against hyperglycemia-induced endothelial dysfunction through p65 and Nrf2. In our studies, applying cell migration assay and tube formation assay, we observed an obvious improvement of endothelial function under MET-treated, as characterized by that MET accelerated GDM-attenuated migration and angiogenesis of HUVECs. And ELISA assay results uncovered that Nrf2 expression level was decreased in GDM placenta, HVUECs and maternal serum comparing with normal group, however activation Nrf2 largely ameliorated tube formation under hyperglycemic condition. Furthermore, MET elevated the Nrf2 expression level and the level of nuclear Nrf2 accumulation in hyperglycemic HUVECs. Besides, preliminary evidence predicted that Nrf2 expression was modulated by transcription factor p65, which was increased in GDM peripheral blood, placenta and HUVECs, and suppression of p65 could recover GDM-induced suppression of angiogenesis. In addition, we also confirmed MET restores the GDM-induced angiogenesis impairment may via downregulation of p65 and upregulation of Nrf2. Taken together, the endothelial protective effect of MET under GDM (HG) conditions could be partly attributed to its role in downregulating p65 and upregulating Nrf2.

SUBMITTER: Sun CC

PROVIDER: S-EPMC7581851 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction <i>via</i> Downregulation of p65 and Upregulation of Nrf2.

Sun Cong Cong CC Lai Ya Nan YN Wang Wen Huan WH Xu Xiao Min XM Li Xiao Qing XQ Wang Hai H Zheng Jia Yong JY Zheng Jian Qiong JQ

Frontiers in pharmacology 20201009

Gestational diabetes mellitus (GDM) causes oxidative stress in mothers and infants and causes vascular endothelial dysfunction, which is a key factor for maternal and fetal cardiovascular diseases in the later stage of GDM, seriously threatening the life and health of mothers and infants. Nowadays, metformin (MET) has been discovered to improve endothelial function, but studies regarding the mechanism of MET improving endothelial cell function and alleviating endothelial function under hyperglyc ...[more]

PMID: 33162888

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Project description:Diabetic cardiovascular complications are characterised by oxidative stress-induced endothelial dysfunction. Uncoupling protein 2 (UCP2) is a regulator of mitochondrial reactive oxygen species (ROS) generation and can antagonise oxidative stress, but approaches that enhance the activity of UCP2 to inhibit ROS are scarce. Our previous studies show that activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin can prevent cardiometabolic disorders. In this study, we conducted experiments in vitro and in vivo to investigate the effect of capsaicin treatment on endothelial UCP2 and oxidative stress. We hypothesised that TRPV1 activation by capsaicin attenuates hyperglycemia-induced endothelial dysfunction through a UCP2-mediated antioxidant effect.TRPV1(-/-), UCP2(-/-) and db/db mice, as well as matched wild type (WT) control mice, were included in this study. Some mice were subjected to dietary capsaicin for 14 weeks. Arteries isolated from mice and endothelial cells were cultured. Endothelial function was examined, and immunohistological and molecular analyses were performed.Under high-glucose conditions, TRPV1 expression and protein kinase A (PKA) phosphorylation were found to be decreased in the cultured endothelial cells, and the effects of high-glucose on these molecules were reversed by the administration of capsaicin. Furthermore, high-glucose exposure increased ROS production and reduced nitric oxide (NO) levels both in endothelial cells and in arteries that were evaluated respectively by dihydroethidium (DHE) and DAF-2 DA fluorescence. Capsaicin administration decreased the production of ROS, restored high-glucose-induced endothelial dysfunction through the activation of TRPV1 and acted in a UCP2-dependent manner in vivo. Administration of dietary capsaicin for 14 weeks increased the levels of PKA phosphorylation and UCP2 expression, ameliorated the vascular oxidative stress and increased NO levels observed in diabetic mice. Prolonged dietary administration of capsaicin promoted endothelium-dependent relaxation in diabetic mice. However, the beneficial effect of capsaicin on vasorelaxation was absent in the aortas of UCP2(-/-) mice exposed to high-glucose levels.TRPV1 activation by capsaicin might protect against hyperglycemia-induced endothelial dysfunction through a mechanism involving the PKA/UCP2 pathway.

Dataset Information

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

Publications

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction <i>via</i> Downregulation of p65 and Upregulation of Nrf2.

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