Abstract
Cardiovascular complications are a major leading cause of mortality in patients suffering from type 2 diabetes mellitus (T2DM). Vascular endothelial dysfunction is a core pathophysiological event in the early stage of T2DM and eventually leads to cardiovascular disease. Vaccarin (VAC), an active flavonoid glycoside extracted from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protection effects. However, little is known about whether VAC is involved in endothelial dysfunction regulation under high glucose (HG) or hyperglycemia conditions. Here, in an in vivo study, we found that VAC attenuated increased blood glucose, increased glucose and insulin tolerance, relieved the disorder of lipid metabolism and oxidative stress, and improved endothelium-dependent vasorelaxation in STZ/HFD-induced T2DM mice. Furthermore, in cultured human microvascular endothelial cell-1 (HMEC-1) cells, we showed that pretreatment with VAC dose-dependently increased nitric oxide (NO) generation and the phosphorylation of eNOS under HG conditions. Mechanistically, VAC-treated HMEC-1 cells exhibited higher AMPK phosphorylation, which was attenuated by HG stimulation. Moreover, HG-triggered miRNA-34a upregulation was inhibited by VAC pretreatment, which is in accordance with pretreatment with AMPK inhibitor compound C (CC). In addition, both reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and VAC abolished HG-evoked dephosphorylation of AMPK and eNOS, increased miRNA-34a expression, and decreased NO production. These results suggest that VAC impedes HG-induced endothelial dysfunction via inhibition of the ROS/AMPK/miRNA-34a/eNOS signaling cascade.
Highlights
Diabetes is a common metabolic disease characterized by hyperglycemia, which causes damage to multi-vessels
In an in vivo study, we found that the body weight of the type 2 diabetes mellitus (T2DM) group slightly decreased, and this could be attenuated by VAC treatment (Figure S1A)
The results of the Glucose Tolerance Test (GTT) showed that blood glucose level at 30, 60, and 120 min after oral administration of glucose was significantly lower in the VAC intervention group than that of the STZ/HFD group (Figure S1D)
Summary
Diabetes is a common metabolic disease characterized by hyperglycemia, which causes damage to multi-vessels. Long-term hyperglycemia, insulin resistance, glucose and lipid metabolism disorder, inflammation and oxidative stress in diabetics can all lead to vascular endothelial cell injury, which eventually causes vascular endothelial dysfunction. Further pathological reactions caused by increased proinflammatory factors, adhesion factors and abnormal smooth muscle cell proliferation have been associated with type 2 diabetes mellitus (T2DM) [6,7,8]. Endothelial cell injury is induced by hydrogen peroxide and HG, this can be reversed by VAC via inhibiting the Notch signaling pathway in the EA. In this study, we examined the effect of VAC on glucose disorder, insulin tolerance and vasorelaxation in mice with T2DM, and further elucidated the roles and molecular mechanisms of VAC in improving vascular endothelial dysfunction and injury under HG or hyperglycemia conditions
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