Angiotensin 1-7 Protects against Angiotensin II-Induced Endoplasmic Reticulum Stress and Endothelial Dysfunction via Mas Receptor.

Dharmani Murugan,Wai Chi Lau,Mohd Rais Mustafa,Yeh Siang Lau,Yu Huang,Xianwu Cheng

doi:10.1371/journal.pone.0145413

Dharmani Murugan, Wai Chi Lau + Show 4 more

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https://doi.org/10.1371/journal.pone.0145413

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Journal: PloS one	Publication Date: Dec 28, 2015
Citations: 44	License type: CC BY 4.0

Affiliation: University of Malaya, Chinese University of Hong Kong

Abstract

Angiotensin 1–7 (Ang 1–7) counter-regulates the cardiovascular actions of angiotensin II (Ang II). The present study investigated the protective effect of Ang 1–7 against Ang II-induced endoplasmic reticulum (ER) stress and endothelial dysfunction. Ex vivo treatment with Ang II (0.5 μM, 24 hours) impaired endothelium-dependent relaxation in mouse aortas; this harmful effect of Ang II was reversed by co-treatment with ER stress inhibitors, l4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) as well as Ang 1–7. The Mas receptor antagonist, A779, antagonized the effect of Ang 1–7. The elevated mRNA expression of CHOP, Grp78 and ATF4 or protein expression of p-eIF2α and ATF6 (ER stress markers) in Ang II-treated human umbilical vein endothelial cells (HUVECs) and mouse aortas were blunted by co-treatment with Ang 1–7 and the latter effect was reversed by A779. Furthermore, Ang II-induced reduction in both eNOS phosphorylation and NO production was inhibited by Ang 1–7. In addition, Ang 1–7 decreased the levels of ER stress markers and augmented NO production in HUVECs treated with ER stress inducer, tunicamycin. The present study provides new evidence for functional antagonism between the two arms of the renin-angiotensin system in endothelial cells by demonstrating that Ang 1–7 ameliorates Ang II-stimulated ER stress to raise NO bioavailability, and subsequently preserves endothelial function.

Highlights

The endoplasmic reticulum (ER) is the key cell organelle responsible for protein translation, folding and trafficking
Disruption in ER homeostasis or function is associated with oxidative stress, inflammatory reaction, hyperglycemia, calcium deprivation, and the exposure to chemicals such as thapsigargin or tunicamycin leads to misfolding and aggregation of proteins within ER lumen; a process known as ER stress, leading to activation of a complex signaling network called the unfolded protein response (UPR), which attempts to restore
The levels of ER stress proteins, p-eIF2α and activating transcription factor 6 (ATF6) were significantly elevated in angiotensin II (Ang II)-treated human umbilical vein endothelial cells (HUVECs), which was normalized by co-treatment with phenylbutyric acid (PBA), tauroursodeoxycholic acid (TUDCA), losartan, and tempol (Fig 1C, 1D and 1E)

Summary

Introduction

The endoplasmic reticulum (ER) is the key cell organelle responsible for protein translation, folding and trafficking. The maintenance of calcium homeostasis, and production and storage of glycogen as well as other macromolecules take place in the ER which is the early site responding to cellular stress [1, 2, 3]. Disruption in ER homeostasis or function is associated with oxidative stress, inflammatory reaction, hyperglycemia, calcium deprivation, and the exposure to chemicals such as thapsigargin or tunicamycin leads to misfolding and aggregation of proteins within ER lumen; a process known as ER stress, leading to activation of a complex signaling network called the unfolded protein response (UPR), which attempts to restore. Angiotensin 1-7 and Endoplasmic Reticulum Stress normal ER function [1, 4]. Recent evidence indicates the involvement of ER stress in diabetes, hypertension, cardiac hypertrophy, atherosclerosis, and ischemic heart disease [5, 6, 7, 8]

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