HLA-B35 upregulates endothelin-1 and downregulates endothelial nitric oxide synthase via endoplasmic reticulum stress 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 in patients with scleroderma, 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 physiological levels via adenoviral vector resulted in significantly increased endothelin-1 (ET-1) and a significantly decreased endothelial NO synthase (eNOS), mRNA, and protein levels. Furthermore, HLA-B35 greatly upregulated expression of chaperones, including heat shock proteins (HSPs) HSP70 (HSPA1A and HSPA1B) and HSP40 (DNAJB1 and DNAJB9), suggesting that HLA-B35 induces the endoplasmic reticulum (ER) stress and unfolded protein response in ECs. Examination of selected mediators of the unfolded protein response, including H chain binding protein (BiP; GRP78), C/Ebp homologous protein (CHOP; GADD153), endoplasmic reticulum oxidase, and protein disulfide isomerase has revealed a consistent increase of BiP expression levels. Accordingly, thapsigargin, a known ER stress inducer, stimulated ET-1 mRNA and protein levels in ECs. This study suggests that HLA-B35 could contribute to EC dysfunction via ER stress-mediated induction of ET-1 in patients with pulmonary hypertension.

• Authors: Stefania Lenna, Danyelle M Townsend, Filemon K Tan, Bagrat Kapanadze, Malgorzata Markiewicz, Maria Trojanowska, Raffaella Scorza
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 184 Issue 9 Pg. 4654-61 (May 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20335527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Endoplasmic Reticulum Chaperone BiP
• Endothelin-1
• HLA-B35 Antigen
• HSPA5 protein, human
• Nitric Oxide Synthase Type III

Topics

• Cell Line
• Cells, Cultured
• Down-Regulation (immunology)
• Endoplasmic Reticulum (enzymology, immunology, metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Endothelin-1 (biosynthesis)
• Endothelium, Vascular (cytology, enzymology, immunology, metabolism)
• HLA-B35 Antigen (physiology)
• Humans
• Hypertension, Pulmonary (enzymology, immunology, metabolism)
• Nitric Oxide Synthase Type III (antagonists & inhibitors, biosynthesis)
• Stress, Physiological (immunology)
• Up-Regulation (immunology)