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Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats

Endoplasmic reticulum (ER) stress contributes to insulin resistance and macro- and microvascular complications associated with diabetes. This study aimed to evaluate the effect of ER stress inhibition on endothelial function in the aorta of type-2 diabetic rats. Type-2 diabetes was developed in male...

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Autores principales: Mustapha, Sagir, Azemi, Ahmad Khusairi, Wan Ahmad, Wan Amir Nizam, Rasool, Aida Hanum Ghulam, Mustafa, Mohd Rais, Mokhtar, Siti Safiah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413505/
https://www.ncbi.nlm.nih.gov/pubmed/36014347
http://dx.doi.org/10.3390/molecules27165107
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author Mustapha, Sagir
Azemi, Ahmad Khusairi
Wan Ahmad, Wan Amir Nizam
Rasool, Aida Hanum Ghulam
Mustafa, Mohd Rais
Mokhtar, Siti Safiah
author_facet Mustapha, Sagir
Azemi, Ahmad Khusairi
Wan Ahmad, Wan Amir Nizam
Rasool, Aida Hanum Ghulam
Mustafa, Mohd Rais
Mokhtar, Siti Safiah
author_sort Mustapha, Sagir
collection PubMed
description Endoplasmic reticulum (ER) stress contributes to insulin resistance and macro- and microvascular complications associated with diabetes. This study aimed to evaluate the effect of ER stress inhibition on endothelial function in the aorta of type-2 diabetic rats. Type-2 diabetes was developed in male Sprague–Dawley rats using a high-fat diet and low-dose streptozotocin. Rat aortic tissues were harvested to study endothelial-dependent relaxation. The mechanisms for acetylcholine-mediated relaxation were investigated using pharmacological blockers, Western blotting, oxidative stress, and inflammatory markers. Acetylcholine-mediated relaxation was diminished in the aorta of diabetic rats compared to control rats; supplementation with TUDCA improved relaxation. In the aortas of control and diabetic rats receiving TUDCA, the relaxation was mediated via eNOS/PI3K/Akt, NAD(P)H, and the K(ATP) channel. In diabetic rats, acetylcholine-mediated relaxation involved eNOS/PI3K/Akt and NAD(P)H, but not the K(ATP) channel. The expression of ER stress markers was upregulated in the aorta of diabetic rats and reduced with TUDCA supplementation. The expression of eNOS and Akt were lower in diabetic rats but were upregulated after supplementation with TUDCA. The levels of MDA, IL-6, and SOD activity were higher in the aorta of the diabetic rats compared to control rats. This study demonstrated that endothelial function was impaired in diabetes, however, supplementation with TUDCA improved the function via eNOS/Akt/PI3K, NAD(P)H, and the K(ATP) channel. The improvement of endothelial function was associated with increased expressions of eNOS and Akt. Thus, ER stress plays a crucial role in the impairment of endothelial-dependent relaxation. Mitigating ER stress could be a potential strategy for improving endothelial dysfunction in type-2 diabetes.
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spelling pubmed-94135052022-08-27 Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats Mustapha, Sagir Azemi, Ahmad Khusairi Wan Ahmad, Wan Amir Nizam Rasool, Aida Hanum Ghulam Mustafa, Mohd Rais Mokhtar, Siti Safiah Molecules Article Endoplasmic reticulum (ER) stress contributes to insulin resistance and macro- and microvascular complications associated with diabetes. This study aimed to evaluate the effect of ER stress inhibition on endothelial function in the aorta of type-2 diabetic rats. Type-2 diabetes was developed in male Sprague–Dawley rats using a high-fat diet and low-dose streptozotocin. Rat aortic tissues were harvested to study endothelial-dependent relaxation. The mechanisms for acetylcholine-mediated relaxation were investigated using pharmacological blockers, Western blotting, oxidative stress, and inflammatory markers. Acetylcholine-mediated relaxation was diminished in the aorta of diabetic rats compared to control rats; supplementation with TUDCA improved relaxation. In the aortas of control and diabetic rats receiving TUDCA, the relaxation was mediated via eNOS/PI3K/Akt, NAD(P)H, and the K(ATP) channel. In diabetic rats, acetylcholine-mediated relaxation involved eNOS/PI3K/Akt and NAD(P)H, but not the K(ATP) channel. The expression of ER stress markers was upregulated in the aorta of diabetic rats and reduced with TUDCA supplementation. The expression of eNOS and Akt were lower in diabetic rats but were upregulated after supplementation with TUDCA. The levels of MDA, IL-6, and SOD activity were higher in the aorta of the diabetic rats compared to control rats. This study demonstrated that endothelial function was impaired in diabetes, however, supplementation with TUDCA improved the function via eNOS/Akt/PI3K, NAD(P)H, and the K(ATP) channel. The improvement of endothelial function was associated with increased expressions of eNOS and Akt. Thus, ER stress plays a crucial role in the impairment of endothelial-dependent relaxation. Mitigating ER stress could be a potential strategy for improving endothelial dysfunction in type-2 diabetes. MDPI 2022-08-11 /pmc/articles/PMC9413505/ /pubmed/36014347 http://dx.doi.org/10.3390/molecules27165107 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mustapha, Sagir
Azemi, Ahmad Khusairi
Wan Ahmad, Wan Amir Nizam
Rasool, Aida Hanum Ghulam
Mustafa, Mohd Rais
Mokhtar, Siti Safiah
Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats
title Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats
title_full Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats
title_fullStr Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats
title_full_unstemmed Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats
title_short Inhibition of Endoplasmic Reticulum Stress Improves Acetylcholine-Mediated Relaxation in the Aorta of Type-2 Diabetic Rats
title_sort inhibition of endoplasmic reticulum stress improves acetylcholine-mediated relaxation in the aorta of type-2 diabetic rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413505/
https://www.ncbi.nlm.nih.gov/pubmed/36014347
http://dx.doi.org/10.3390/molecules27165107
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