Protective Effect of Astragaloside IV on High Glucose-Induced Endothelial Dysfunction via Inhibition of P2X7R Dependent P38 MAPK Signaling Pathway.

Bin Leng,Yang Sun,Kun Zhao,Cong Li,Ling Zhang,Mei-Li Lu,Hong-Xin Wang

doi:10.1155/2020/5070415

Abstract

Vascular endothelial dysfunction is associated with increased mortality in patients with diabetes. Astragaloside IV (As-IV) is a bioactive saponin with therapeutic potential as an anti-inflammatory and antiendothelial dysfunction. However, the underlying mechanism for how As-IV ameliorated endothelial dysfunction is still unclear. Therefore, in this study, we examined the protective effect of As-IV against endothelial dysfunction and explored potential molecular biology mechanism. In vivo, rats were intraperitoneally injected with streptozotocin (STZ) at a dose of 65 mg/kg body weight to establish a diabetic model. In vitro studies, rat aortic endothelial cells (RAOEC) were pretreated with As-IV, SB203580 (p38 MAPK inhibitor) for 2 h prior to the addition of high glucose (33 mM glucose). Our findings indicated that As-IV improved impaired endothelium-dependent relaxation and increased the levels of endothelial NO synthase (eNOS) and nitric oxide (NO) both in vivo and in vitro. Besides, As-IV treatment inhibited the elevated inflammation and oxidative stress in diabetic model both in vivo and in vitro. Moreover, As-IV administration reversed the upregulated expression of P2X7R and p-p38 MAPK in vivo and in vitro. Additionally, the effects of both P2X7R siRNA and SB203580 on endothelial cells were similar to As-IV. Collectively, our study demonstrated that As-IV rescued endothelial dysfunction induced by high glucose via inhibition of P2X7R dependent p38 MAPK signaling pathway. This provides a theoretical basis for the further study of the vascular endothelial protective effects of As-IV.

Highlights

Diabetes is a chronic metabolic disease characterized by hyperglycemia and widely disturbs the normal metabolic activity of microvascular and macrovascular
Immunofluorescence results showed that Astragaloside IV (As-IV) increased high glucose-induced decrease of endothelial nitric oxide (NO) synthase (eNOS) in the aortic endothelial cells (Figure 1(d) and 1(e)), while western blot results showed that As-IV reversed the reduction of eNOS expression in the aorta (Figure 1(f)) of STZ-induced diabetic rats
After 8 weeks of intraperitoneal injection of STZ in rats, we found that vascular endothelium-dependent relaxation to Ach was diminished, and this change was rescued by As-IV

Summary

Introduction

Diabetes is a chronic metabolic disease characterized by hyperglycemia and widely disturbs the normal metabolic activity of microvascular and macrovascular. Endothelial dysfunction, which is manifested by the impairment of nitric oxide (NO)-mediated endothelium-dependent, has been recognized as a common and essential factor in the pathogenesis of diabetic microvascular and macrovascular diseases [2, 3]. Inflammation and oxidative stress are the major triggers for cardiovascular disease and are the main culprits leading to endothelial dysfunction. Endothelial dysfunction is a complex pathological process that is regulated by multiple regulators, including the activation of P38 mitogen-activated protein kinase (p38 MAPK), which accelerates the occurrence of inflammation and oxidative stress [8, 9].

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