Endothelin-1, the Unfolded Protein Response, and Persistent Inflammation

Division of Pulmonary, and Critical Care Medicine, Department of Pediatrics, University of Colorado at Denver, Aurora, 80138, USA.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 07/2011; 46(1):14-22. DOI: 10.1165/rcmb.2010-0506OC
Source: PubMed


Endothelin-1 is a potent vasoactive peptide that occurs in chronically high levels in humans with pulmonary hypertension and in animal models of the disease. Recently, the unfolded protein response was implicated in a variety of diseases, including pulmonary hypertension. In addition, evidence is increasing for pathological, persistent inflammation in the pathobiology of this disease. We investigated whether endothelin-1 might engage the unfolded protein response and thus link inflammation and the production of hyaluronic acid by pulmonary artery smooth muscle cells. Using immunoblot, real-time PCR, immunofluorescence, and luciferase assays, we found that endothelin-1 induces both a transcriptional and posttranslational activation of the three major arms of the unfolded protein response. The pharmacologic blockade of endothelin A receptors, but not endothelin B receptors, attenuated the observed release, as did a pharmacologic blockade of extracellular signal-regulated kinases 1 and 2 (ERK-1/2) signaling. Using short hairpin RNA and ELISA, we observed that the release by pulmonary artery smooth muscle cells of inflammatory modulators, including hyaluronic acid, is associated with endothelin-1-induced ERK-1/2 phosphorylation and the unfolded protein response. Furthermore, the synthesis of hyaluronic acid induced by endothelin-1 is permissive for persistent THP-1 monocyte binding. These results suggest that endothelin-1, in part because it induces the unfolded protein response in pulmonary artery smooth muscle cells, triggers proinflammatory processes that likely contribute to vascular remodeling in pulmonary hypertension.

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Available from: David Dunbar Ivy, Oct 01, 2015
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    • "In MCT rats, significant increases in lung proteins governing unfolded protein response, serotonin biology, and chloride channels were documented. Subsequent to that study, the unfolded protein response[67] [68] [69] and chloride channels[70] [71] have become major research themes for several investigators, thus validating the discovery value of proteomics in PH. Furthermore, differences in protein folding proteins[72], proteasome subunits[73], and chloride channel protein expression[74] in lungs from rats with PH compared to controls have been documented by independent groups, a testimony to the robustness of proteomics. "
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    ABSTRACT: Pulmonary hypertension (PH) is a fatal syndrome that arises from a multifactorial and complex background, is characterized by increased pulmonary vascular resistance and right heart afterload, and often leads to cor pulmonale. Over the past decades, remarkable progress has been made in reducing patient symptoms and delaying the progression of the disease. Unfortunately, PH remains a disease with no cure. The substantial heterogeneity of PH continues to be a major limitation to the development of newer and more efficacious therapies. New advances in our understanding of the biological pathways leading to such a complex pathogenesis will require the identification of the important proteins and protein networks that differ between a healthy lung (or right ventricle) and a remodeled lung in an individual with PH. In this article, we present the case for the increased use of proteomics-the study of proteins and protein networks- as a discovery tool for key proteins and protein networks operational in the PH lung. We review recent applications of proteomics in PH, and summarize the biological pathways identified. Finally, we attempt to presage what the future will bring with regard to proteomics in PH and offer our perspectives on the prospects of developing personalized proteomics and custom-tailored therapies.
    PROTEOMICS - CLINICAL APPLICATIONS 02/2015; 9(1-2). DOI:10.1002/prca.201400157 · 2.96 Impact Factor
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    • "Compared to controls, PAH patients’ PBMC had higher expression of these markers, which in the case of the unfolded protein response effectors DnaJB and BiP, correlated to inflammation (IL-6 levels) and disease severity (pa). Importantly, these studies seem to corroborate an emerging concept of cell stress in PAH that is being borne out in animal models of PAH (92). These results provide evidence that analysis of circulating white blood cells by flow cytometric quantification and subsequent gene expression characterization represent potentially important blood tests that could be integratively applied to current diagnostic and prognostic workups in children with PAH. "
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    ABSTRACT: Therapeutic approaches in pediatric pulmonary arterial hypertension (PAH) are based primarily on clinician experience, in contrast to the evidence-based approach in adults with pulmonary hypertension. There is a clear and present need for non-invasive and objective biomarkers to guide the accurate diagnosis, treatment, and prognosis of this disease in children. The multifaceted spectrum of disease, clinical presentation, and association with other diseases makes this a formidable challenge. However, as more progress is being made in the understanding and management of adult PAH, the potential to apply this knowledge to children has never been greater. This review explores the state of the art with regard to non-invasive biomarkers in PAH, with an eye toward those adult PAH biomarkers potentially suitable for application in pediatric PAH.
    Frontiers in Pediatrics 02/2014; 2:7. DOI:10.3389/fped.2014.00007
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    • "When excessive amounts of abnormally folded proteins accumulate within the ER and cytosol of cells, aggregation occurs and cell death pathways are ultimately activated.[19] ER stress has been investigated in various disease contexts and has been linked to the pathobiology of neurodegenerative disorders, atherosclerosis, alcoholic liver disease, viral infection, rheumatoid arthritis, idiopathic pulmonary fibrosis,[20–22] and most recently, severe pulmonary artery hypertension.[23–25] "
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    ABSTRACT: Pulmonary hypertension remains an important cause of morbidity and mortality. Although there is currently no cure, descriptions of defective intracellular trafficking and protein misfolding in vascular cell models of pulmonary hypertension have been recently reported. We tested the hypothesis that activation of the unfolded protein response (UPR) would be associated with the development of severe PH. We investigated activation of the UPR in archival tissues from patients with severe PH, and in the monocrotaline-induced rat model of severe PH. We tested the ability of a pharmacologic agent capable of modulating the UPR to prevent and reverse pulmonary hypertension. We found evidence of an active UPR in archival tissue from humans with PH, but not in control lungs. Similarly, monocrotaline-treated rats demonstrated a significant difference in expression of each of the major arms of the UPR compared to controls. Interestingly, the UPR preceded the appearance of macrophages and the development of lung vascular remodeling in the rats. Treatment of monocrotaline rats with salubrinal, a modulator of the PERK arm of the UPR, attenuated PH and was associated with a decrease in lung macrophages. In culture, pulmonary artery smooth muscle cells with UPR induction produced IL-6 and CCL-2/MCP-1, and stimulated macrophage migration. These effects were abolished by pretreatment of cells with salubrinal. These data support the hypothesis that the UPR may play a role in the pathogenesis of inflammatory vascular remodeling and PH. As such, understanding the functional contributions of the UPR in the setting of PH may have important therapeutic implications.
    04/2012; 2(2):229-40. DOI:10.4103/2045-8932.97613
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