Activation of Nrf2-mediated anti-oxidant genes by antrodin C prevents hyperglycemia-induced senescence and apoptosis in human endothelial cells.

Kumar K.J Senthil,Sheng-Yang Wang,Vani M Gokila

doi:10.18632/oncotarget.19951

Kumar K.J Senthil, Sheng-Yang Wang + Show 1 more

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https://doi.org/10.18632/oncotarget.19951

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Abstract

In the present study, we investigated the effects of antrodin C (ADC), a maleimide derivative isolated from mycelia of Antrodia cinnamomea, on high glucose (HG, 30 mM)-accelerated endothelial dysfunction in vitro. HG-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) was significantly ameliorated by ADC. In addition, treatment with ADC significantly prevented HG-induced senescence, growth arrest at the G1-S transition phase and apoptosis in HUVECs. Moreover, the increased level of intracellular reactive oxygen species (ROS) under HG condition was significantly ameliorated by ADC. Further analysis revealed that ADC-mediated anti-oxidant effects were due to up-regulation of cellular anti-oxidant genes, such as HO-1 and NQO-1 via promotion of the transcriptional activity of Nrf2, which was further confirmed by the failure of ADC to protect HUVECs from HG-induced dysfunction under HO-1 inhibition or Nrf2 silencing. Furthermore, hyperosmotic glucose (HOG, 60 mM)-induced uncontrolled production of ROS, rapid apoptotic cell death and HUVEC injury were significantly prevented by ADC, whereas these preventive effects were barely observed in HO-1 inhibited or Nrf2 silenced cells. Taken together, these results suggest that ADC may represent a promising intervention in diabetic-associated cardiovascular diseases by activating the Nrf2-dependent cellular anti-oxidant defense system.

Highlights

Hyperglycemia, a characteristic feature of diabetes mellitus (DM) and metabolic syndrome has emerged as a major health problem that rapidly causes vascular and organ dysfunction [1]
Given that hyperglycemia-induced endothelial cell dysfunction is a key event in the onset and progression of Cardiovascular disease (CVD), protection of vascular endothelial cells from such dysfunction represents an important strategy for the diagnosis of CVD
We previously reported that Antrodin C, a maleimide derivative isolated from the mycelia of A. cinnamomea inhibits TGF-βinduced breast cancer cell metastasis via inhibition of epithelial-to-mesenchymal transition in vitro [29]

Summary

Introduction

Hyperglycemia, a characteristic feature of diabetes mellitus (DM) and metabolic syndrome has emerged as a major health problem that rapidly causes vascular and organ dysfunction [1]. It has been estimated that by 2030, developing countries in Asia and the Middle East will have the largest increases in the prevalence of type-2 DM due to modernization of lifestyles and nutrition [2]. Common complications of diabetes mellitus include age-associated diseases, such as vascular ageing, hypertension and atherosclerosis [3]. Vascular endothelial cells are highly specialized and active cells that regulate thrombosis and inflammatory processes. Alterations in endothelial cells and the vasculature play a critical role in the pathogenesis of a broad spectrum of the most serious human diseases [4]. Vascular endothelial cell senescence, which is highly associated with diabetes mellitus [5], promotes vascular dysfunction and is accompanied by increased vascular risk [6]

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