3\u2032,4\u2032-dihydroxyflavonol ameliorates endoplasmic reticulum stress-induced apoptosis and endothelial dysfunction in mice

Yeh Siang Lau,Stanley M H Chan,Terence P Herbert,Ker Woon Choy,Mohd Rais Mustafa,Simon Potocnik,Owen L Woodman

doi:10.1038/s41598-018-19584-8

Yeh Siang Lau, Stanley M H Chan + Show 5 more

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https://doi.org/10.1038/s41598-018-19584-8

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Abstract

Endoplasmic reticulum (ER) stress has been implicated in the development of hypertension 3 through the induction of endothelial impairment. As 3′,4′-dihydroxyflavonol (DiOHF) 4 reduces vascular injury caused by ischaemia/reperfusion or diabetes, and flavonols have been demonstrated to attenuate ER stress, we investigated whether DiOHF can protect mice from ER stress-induced endothelial dysfunction. Male C57BLK/6 J mice were injected with tunicamycin to induce ER stress in the presence or absence of either DiOHF or tauroursodeoxycholic acid (TUDCA), an inhibitor of ER stress. Tunicamycin elevated blood pressure and impaired endothelium-dependent relaxation. Moreover, in aortae there was evidence of ER stress, oxidative stress and reduced NO production. This was coincident with increased NOX2 expression and reduced phosphorylation of endothelial nitric oxide synthase (eNOS) on Ser1176. Importantly, the effects of tunicamycin were significantly ameliorated by DiOHF or TUDCA. DiOHF also inhibited tunicamycin-induced ER stress and apoptosis in cultured human endothelial cells (HUVEC). These results provide evidence that ER stress is likely an important initiator of endothelial dysfunction through the induction of oxidative stress and a reduction in NO synthesis and that DiOHF directly protects against ER stress- induced injury. DiOHF may be useful to prevent ER and oxidative stress to preserve endothelial function, for example in hypertension.

Highlights

The endoplasmic reticulum (ER) is required for the synthesis of all membrane and secretory proteins
Co-treatment with DiOHF or tauroursodeoxycholic acid (TUDCA) significantly reversed this effect to ~106–109 mmHg for SBP, whereas DiOHF treatment alone had no effect on SBP compared to the untreated control group (Fig. 1A)
We demonstrated that DiOHF effectively protects the endothelium against Endoplasmic reticulum (ER) stress-mediated apoptosis in mice, accompanied by an antioxidant effect

Summary

Introduction

The endoplasmic reticulum (ER) is required for the synthesis of all membrane and secretory proteins. Disturbances in ER homeostasis that perturb protein folding, such as ER calcium depletion, changes in the ER redox state and/or the rate of protein synthesis exceeding the rate of folding, can lead to the accumulation of unfolded proteins within the ER resulting in ER stress[1,2] This in turn triggers the unfolded protein response (UPR), an adaptive response initiated by the activation of three ER transmembrane proteins i.e. 1) inositol-requiring enzyme 1 (IRE1), 2) protein kinase RNA–like endoplasmic reticulum kinase (PERK), and 3) activating transcription factor 6 (ATF6)[3]. 3′,4′-Dihydroxyflavonol (DiOHF) is a synthetic flavonol that exhibits antioxidant activity and has been shown to improve endothelial function in aortae in the presence of oxidative stress[15,16]. The present research explores, for the first time, the effects of DiOHF in ER stress-induced apoptosis and endothelial dysfunction in mice

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