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HLA-B35 upregulates ET-1 and downregulates eNOS via ER stresss response in endothelial cells

ABSTRACT: The presence of the HLA-B35 allele has emerged as an important risk factor for the development of isolated pulmonary hypertension (iPHT) in patients with Scleroderma (SSc), however the mechanisms underlying this association have not been fully elucidated. The goal of our study was to determine the molecular mechanisms that mediate the biological effects of HLA-B35 in endothelial cells (ECs). Our data demonstrate that HLA-B35 expression at the physiological levels using via adenoviral vector resulted in a significantly increased endothelin-1 (ET-1) and a significantly decreased endothelial nitric oxide synthase (eNOS) mRNA and protein levels. Furthermore, HLA-B35 greatly upregulated expression of cytoplasmic chaperones, including heat shock proteins (HSPs) HSP70 (HSPA1A and HSPA1B) and HSP40 (DNAJB1 and DNAJB9), suggesting that HLA-B35 induced the ER stress and unfolded protein response (UPR) in ECs. Examination of selected mediators of the UPR response, including BiP (GRP78), CHOP (GADD153), ERO1 (endoplasmic reticulum oxidase) and PDI (protein disulfide isomerase) has revealed a consistent increase of BiP expression levels. Accordingly, Thapsigargin (TG), a known ER stress inducer, stimulated ET-1 mRNA and protein levels in ECs. This study suggests that HLA-B35 could contribute to endothelial cell dysfunction via ER stress mediated induction of ET-1 in patients with PHT.

ORGANISM(S): Homo sapiens

PROVIDER: GSE20055 | GEO | 2010/03/01

SECONDARY ACCESSION(S): PRJNA124325

REPOSITORIES: GEO

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Project description:A data-entrained computational model for testing the regulatory logic of the vertebrate unfolded protein response This model is described in the article: A data-entrained computational model for testing the regulatory logic of the vertebrate unfolded protein response. Diedrichs DR, Gomez JA, Huang CS, Rutkowski DT, Curtu R. Mol. Biol. Cell 2018 Apr; : mbcE17090565 Abstract: The vertebrate unfolded protein response (UPR) is characterized by multiple interacting nodes among its three pathways, yet the logic underlying this regulatory complexity is unclear. To begin to address this issue, we created a computational model of the vertebrate UPR that was entrained upon and then validated against experimental data. As part of this validation, the model successfully predicted the phenotypes of cells with lesions in UPR signaling, including a surprising and previously unreported differential role for the eIF2? phosphatase GADD34 in exacerbating severe stress but ameliorating mild stress. We then used the model to test the functional importance of a feed-forward circuit within the PERK/CHOP axis, and of cross-regulatory control of BiP and CHOP expression. We found that the wiring structure of the UPR appears to balance the ability of the response to remain sensitive to ER stress yet also to be rapidly deactivated by improved protein folding conditions. This model should serve as a valuable resource for further exploring the regulatory logic of the UPR. This model is hosted on BioModels Database and identified by: MODEL1803300000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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HLA-B35 upregulates ET-1 and downregulates eNOS via ER stresss response in endothelial cells

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