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

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 ?M, 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-eIF2? 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.

SUBMITTER: Murugan D

PROVIDER: S-EPMC4692500 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Murugan Dharmani D Lau Yeh Siang YS Lau Chi Wai CW Mustafa Mohd Rais MR Huang Yu Y

PloS one 20151228 12

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 ...[more]

PMID: 26709511

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Project description:BackgroundCisplatin (CDDP), a widely used chemotherapeutic agent, can induce excessive granulosa cell apoptosis, follicle loss and even premature ovarian insufficiency (POI). However, the mechanism remains elusive, although some studies have indicated the involvement of endoplasmic reticulum stress (ERS). The aim of our study was to investigate the possible mechanism ERS in CDDP-induced granulosa cell apoptosis and follicle loss.MethodsA POI mouse model was generated by CDDP. The ovaries samples were collected and processed for isobaric tags for relative and absolute quantification analysis (iTRAQ) to screen out our interested proteins of HSPA5 and HSP90AB1, and the decline in their expression were verified by a real-time quantitative PCR and a western blotting assay. In vitro, human granulosa cells, KGN and COV434 cells were transfected with siRNA targeting HSPA5 and HSP90AB1 and then treated with CDDP, or treated with CDDP with/without CDDP+?4-phenylbutyric acid (4-PBA) and 3-methyladenine (3-MA). The levels of ERS, autophagy and apoptosis were evaluated by western blotting, DALGreen staining and flow cytometry. In vivo, ovaries from mice that received intraperitoneal injections of saline, CDDP, CDDP+?4-PBA and CDDP+?3-MA were assayed by immunofluorescence, hematoxylin and eosin (H&E) staining for follicle counting, and terminal-deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining for cell apoptosis assay. The plasma hormone levels were measured by an enzyme-linked immunosorbent assay (ELISA) kit.ResultsWe have clarified the relationships between ERS, autophagy, and apoptosis in CDDP-induced granulosa cell apoptosis, both in vitro and in vivo. Alleviating ERS by inhibiting HSPA5 and HSP90AB1 attenuated CDDP-induced autophagy and apoptosis. 4-PBA treatment significantly attenuated CDDP-induced cell autophagy and apoptosis in cultured KGN and COV434 cells. However, inhibiting cell autophagy with 3-MA negligibly restored the CDDP-induced changes in ERS and apoptosis. In vivo experiments also demonstrated that treatment with 4-PBA, but not 3-MA, prevented CDDP-induced ovarian damage and hormone dysregulation.ConclusionsCDDP-induced ERS could promote autophagy and apoptosis in granulosa cells, causing excessive follicle loss and endocrine disorders. Alleviation of ERS with 4-PBA, but not of autophagy with 3-MA, protect against CDDP-induced granulosa cell apoptosis and ovarian damage. Thus, 4-PBA can be used to protect the ovary during chemotherapy in women.

Project description:BackgroundWhite adipose tissue can be classified based on its location as subcutaneous and visceral fat, and the latter accumulation is reported to be more detrimental to metabolism. Endoplasmic reticulum (ER) stress has been demonstrated to regulate lipogenesis. The peptide angiotensin(1-7) [Ang(1-7)], which can be produced from angiotensin II (AngII) by angiotensin-converting enzyme 2 (ACE2), plays its role through Mas receptor, also participates in the regulation of lipid metabolism in adipose tissue, however, whether ER stress is involved in the mechanism remains unclear. Therefore, we aimed to explore the role of Ang(1-7) pathway in regulating visceral adipose tissue expansion and ER stress.MethodsACE2 knockout (KO), Mas KO and C57BL/6 J mice were fed with high fat diet. Db/db mice were treated with either normal saline, Ang(1-7) or Ang(1-7) combined with Mas receptor inhibitor A779 using mini osmotic pumps. Fat mass was weighted, fat distribution was evaluated by MRI, and lipid profile and adipokines in epididymal adipose tissue were measured by ELISA kits, and histology of epididymal adipose tissue was also analyzed in multiple animal models. Additionally, differentiated 3T3-L1 cells were pre-loaded with palmitic acid to induce ER stress, then treated with drugs as those administrated to db/db mice. ER stress and lipogenesis related proteins in mice adipose and differentiated 3T3L-1 cells were analyzed by Western blot.ResultsACE2 or Mas KO mice exhibited increased visceral adipose tissue, adipocyte size and protein expression of lipogenesis and ER stress related markers in epididymal adipose tissue compared to wild-type mice. Db/db mice treated with Ang(1-7) displayed decreased visceral fat mass, adipocyte size and protein expression of lipogenesis and ER stress markers in epididymal adipose tissue compared to those treated with normal saline, while A779 partly attenuated these effects. Additionally, Ang(1-7) improved ER stress and lipogenesis markers in differentiated 3T3-L1 cells pre-loaded with palmitic acid.ConclusionsOur findings indicated that Ang(1-7) attenuated visceral adipose tissue expansion and lipogenesis by suppression of ER stress via Mas receptor. The present study provides a potential perspective for Ang(1-7) for the therapeutics of obesity and related disorders.

Dataset Information

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

Publications

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

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