Abstract
Objective: Liraglutide (LIRA), a Glucagon-like peptide-1 (GLP-1) receptor agonist, showed potential vascular protective effects with the mechanism remained incompletely understood. Therefore, this study aimed to investigate whether LIRA exerts its effect on vascular endothelial function in rats with type 2 diabetes mellitus (T2DM) via caveolin-1/ endothelial oxide synthase (eNOS) expression. Methods: T2DM rats were used as study subjects and randomly divided into four groups: 1) Veh group, 2) Veh+LIRA group, 3) T2DM group, and 4) T2DM+LIRA group. All rats received either saline or LIRA 0.2 mg/kg (by i.p. injection) per day for 4 weeks. After the model was successfully established, vascular endothelial function was determined the effect of vasodilator to mesenteric artery rings. Immunofluorescence and western blot were performed to understand the molecular mechanism. Cultured HUVECs with small interfering RNA (siRNA) under high glucose (HG), NO concentration, and western blot were performed to understand the molecular mechanism between LIRA and vascular endothelial function. Results: Based on our results, the LIRA reduced hyperglycemia and ameliorated vascular endothelial dysfunction in type 2 diabetic mice. LIRA activated eNOS phosphorylation, suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation of mesenteric arteries. Besides, from its anti-oxidative capacity, LIRA activated eNOS to dilate the mesenteric arteries via the downregulation of Cav-1. Conclusion: LIRA ameliorates vascular endothelial dysfunction in rats with type 2 diabetes mellitus via anti-oxidative and activated eNOS by downregulated Cav-1.
Highlights
Type 2 diabetes mellitus (T2DM), is a type of disease in which clinical manifestations are mainly heterogeneity of insulin resistance with relative insulin deficiency
Establishment and Characterization of the Rat Type 2 Diabetic Models: After 8 weeks of HFSD, blood glucose levels were not increased significantly, while insulin levels and insulin resistance were successfully elicited of the T2DM group (P < 0.01, Fig-1a, Fig-1b, and Fig-1c)
The data are shown as the mean ± SEM; n =3 repeats per group. **p
Summary
Type 2 diabetes mellitus (T2DM), is a type of disease in which clinical manifestations are mainly heterogeneity of insulin resistance with relative insulin deficiency. Original Article peripheral vascular disease) and microvascular complications. Among this vasculopathy, endothelial dysfunction is thought to be the early event initiated by metabolic stresses, including hyperglycemia, insulin resistance [1]. Cav-1, the principal component of caveolae, is abundantly expressed in many different kinds of cell types, including endothelial cells, vascular smooth muscle (VSM), adipocytes, and fibroblasts. GLP-1 infusion can increase acetylcholineinduced vasodilatation, improves flow-mediated dilatation, muscle microvascular recruitment and glucose use independent of insulin secretion via endothelial eNOS activation. As the American Diabetes Association (ADA) reported, insulin plus liraglutide was highly recommended to treat the T2DM patients because it can significantly improve the patients’ condition, especially with glucose-lowering actions and less weight gain and hypoglycemia compared with intensified insulin regimens [5]
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