Acacetin improves endothelial dysfunction and aortic fibrosis in insulin-resistant SHR rats by estrogen receptors

Qi Zhang,Peipei Yuan,Yang Fu,Yaxin Wei,Weisheng Feng,Xiaoke Zheng,Liyuan Gao,Ying Hou

doi:10.1007/s11033-020-05746-3

Qi Zhang, Peipei Yuan + Show 6 more

Open Access

https://doi.org/10.1007/s11033-020-05746-3

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Abstract

The aim of the work was to investigate the effects of acacetin on endothelial dysfunction and aortic fibrosis in insulin-resistant SHR rats and explore its mechanism. Seven-week-old male spontaneously hypertensive rats (SHR) were selected to establish a rat model of hypertension with insulin resistance induced by 10% fructose. The nuclear factor kappa B p65 (NF-κB p65) and Collagen I were observed by Immunohistochemistry. Immunofluorescence was used to observe estrogen receptor-alpha (ERα), estrogen receptor-beta (ERβ), and G protein-coupled receptor 30 (GPR30). Western blotting was used to detect interleukin (IL-1β), Arginase 2 (ARG2), Nostrin, endothelial nitric oxide synthase (eNOS), TGF-β, Smad3, ERK pathway proteins such as p-c-Raf, p-MEK1/2, p-ERK, ERK, p-P90RSK and p-MSK1. We found that acacetin did have an improvement on endothelial dysfunction and fibrosis. Meanwhile, it was also found to have a significant effect on the level of estrogen in this model by accident. Then, the experiment of uterine weight gain in mice confirmed that acacetin had a certain estrogen-like effect in vivo and played its role through the estrogen receptors pathway. In vitro experience HUVEC cells were stimulated with 30 mM/L glucose and 100 mM/L NaCl for 24 h to establish the endothelial cell injury model. HUVEC cells were treated with 1 μM/L estrogen receptors antagonist (ICI 182780) for 30 min before administration. Cell experiments showed that acacetin could reduce the apoptosis of HUVEC cells, the levels of inflammatory cytokines and the expression of TGF-β, Collagen I and Smad3 in endothelial cell injury model. After treatment with ICI 182780, the improvement of acacetin was significantly reversed. The results showed that acacetin relieved endothelial dysfunction and reduced the aortic fibrosis in insulin-resistant SHR rats by reducing the release of inflammatory factors and improving vasodilatory function through estrogen signaling pathway.

Highlights

Hypertension is a major public health problem in the world, endangering people’s life and health
Effects of acacetin on aortic structure and function in spontaneously hypertensive rats (SHR) rats with insulin resistance Observation under light microscope showed that the aortic wall of normal group rats was of moderate thickness, vascular endothelial cells and smooth muscle cells were evenly distributed, elastic fibers were clear and complete, arranged in a ring, and the outer membrane was thin layer of loose connective tissue
Aortic wall thickening was improved and endothelial cells and smooth muscle cells returned to normal, suggesting that acacetin could improve the morphological damage of aortic wall in rats (Fig. 2)

Summary

Introduction

Hypertension is a major public health problem in the world, endangering people’s life and health. According to the recently published China cardiovascular disease news 2018, there are currently about 245 million patients with hypertension in China. The prevalence rate in adults is as high as 23.2% and the incidence of insulin resistance in patients. Cardiovascular diseases have a high incidence of morbidity and mortality, one of the main causes is vascular endothelial dysfunction, that is, endothelial-dependent vascular diastolic dysfunction, resulting in reduced vascular compliance and reduced blood flow [3]. Vascular endothelial dysfunction is manifested in impaired endothelial barrier function, resulting in the muscle layer being damaged by various growth factors or inflammatory factors. It is manifested in impaired vasodilation, vascular remodeling, imbalance of coagulation and anticoagulant mechanism, etc.[4]

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