Inhibition of endoplasmic reticulum stress improves coronary artery function in the spontaneously hypertensive rats.

Soo-Kyoung Choi,Mihwa Lim,Young-Ho Lee,Seon-Hee Byeon

doi:10.1038/srep31925

Soo-Kyoung Choi, Mihwa Lim + Show 2 more

Open Access

https://doi.org/10.1038/srep31925

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Journal: Scientific reports	Publication Date: Aug 1, 2016
Citations: 51	License type: CC BY 4.0

Affiliation: Yonsei University

Abstract

Endoplasmic reticulum (ER) stress has been shown to play a critical role in the pathogenesis of cardiovascular complications. However, the role and mechanisms of ER stress in hypertension remain unclear. Thus, we hypothesized that enhanced ER stress contributes to the maintenance of hypertension in spontaneously hypertensive rats (SHRs). Sixteen-week old male SHRs and Wistar Kyoto Rats (WKYs) were used in this study. The SHRs were treated with ER stress inhibitor (Tauroursodeoxycholic acid; TUDCA, 100 mg/kg/day) for two weeks. There was a decrease in systolic blood pressure in SHR treated with TUDCA. The pressure-induced myogenic tone was significantly increased, whereas endothelium-dependent relaxation was significantly attenuated in SHR compared with WHY. Interestingly, treatment of ER stress inhibitor normalized myogenic responses and endothelium-dependent relaxation in SHR. These data were associated with an increase in expression or phosphorylation of ER stress markers (Bip, ATF6, CHOP, IRE1, XBP1, PERK, and eIF2α) in SHRs, which were reduced by TUDCA treatment. Furthermore, phosphorylation of MLC20 was increased in SHRs, which was reduced by the treatment of TUDCA. Therefore, our results suggest that ER stress could be a potential target for hypertension.

Highlights

Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is normally produced endogenously in the liver[14]
The main findings of this study are (1) endoplasmic reticulum (ER) stress inhibitor, TUDCA, decreased blood pressure in spontaneously hypertensive rats (SHRs); (2) myogenic response and endothelium-dependent relaxation were impaired in coronary arteries from SHRs and the inhibition of ER stress normalized myogenic response and endothelium-dependent relaxation in SHRs; (3) the ER stress sensors were up-regulated in the coronary arteries from SHRs, which were reduced by treatment of TUDCA; (4) phosphorylation of MLC20 was increased in SHRs, and were decreased by TUDCA treatment
These results suggest that increased ER stress is responsible for coronary artery dysfunction in SHRs, likely through up-regulation of all three UPR branches including PERK, ATF6, and IRE1

Summary

Introduction

Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is normally produced endogenously in the liver[14]. TUDCA has long been used as a bile acid replacement therapy for the treatment of cholestasis and hepatocellular necrosis[15]. Its effects have been reported in pulmonary hypertension[16] and cardiovascular disease such as myocardial contractile dysfunction[17], myocarditis[16,17,18]. The modulatory effects of TUDCA in hypertension remain unclear. The present study investigated whether ER stress is increased www.nature.com/scientificreports/. In the coronary arteries of spontaneously hypertensive rats (SHRs) and treatment of TUDCA could alleviate the increased ER stress and normalize the elevated blood pressure in SHRs

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Conclusion