Abstract
Insulin resistance and type 2 diabetes mellitus (T2DM) are highly prevalent around the world. Elevated concentrations of free fatty acids (FFAs) are closely related to insulin resistance and T2DM. P2X7 receptor is an ion channel gated by ATP, which is implicated in various scenarios including immune response, pain, and inflammation. In this study, we have explored whether P2X7 receptor is involved in pathological changes in human umbilical vein endothelial cells (HUVECs) induced by high FFA treatment, and the potential beneficial effects of evodiamine. Evodiamine could effectively suppress the enhanced expression of P2X7 receptor caused by high FFAs at both mRNA and protein levels. In addition, high FFA-induced cytotoxicity, the upregulated release of ATP, and production of reactive oxygen species (ROS) could be ameliorated by evodiamine in HUVECs. Evodiamine could also reverse the decreased NO formation and the increased adhesive events of immune cells at high FFAs. Moreover, evodiamine inhibited P2X7-dependent TNF-α expression and ERK 1/2 phosphorylation due to high FFAs. All these results indicated that evodiamine could correct the upregulated expression of P2X7 receptor induced under high FFA condition in HUVECs, and consequently suppressed oxidative stress and inflammatory responses.
Highlights
Inflammation has been regarded as a risk factor for the development of insulin resistance and type 2 diabetes mellitus (T2DM) [1, 2]
Recent studies have found that concentrations of plasma free fatty acids (FFAs) were increased under the condition of impaired endothelial dysfunction and insulin resistance, suggesting that high FFAs had some adverse effects on endothelial cells [25, 26]
Published studies revealed that reduced vascular Nitric oxide (NO) bioactivity and endothelial dysfunction would occur when superoxide production was increased in experimental models of diabetes [27]
Summary
Inflammation has been regarded as a risk factor for the development of insulin resistance and type 2 diabetes mellitus (T2DM) [1, 2]. Insulin resistance and T2DM are often accompanied by increased plasma levels of free fatty acids (FFAs), hyperinsulinemia, hyperglycemia, and atherosclerosis [3]. Vascular endothelial cells play an important role in vascular regulation, endocrine function, and maintaining cardiovascular homeostasis [4, 5]. Endothelial damage is a fundamental event for the development of atherosclerosis. The risk of vascular diseases is enhanced in the context of hyperinsulinemia, which occurs in blood glucose poorly controlled diabetic patients [6]. Normal functions of endothelial cells are crucial to prevent insulin resistance or diabetes-induced large vessel atherosclerosis and the microvascular damage
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