Document Detail

Endothelin-1, the unfolded protein response, and persistent inflammation: role of pulmonary artery smooth muscle cells.
MedLine Citation:
PMID:  21778413     Owner:  NLM     Status:  MEDLINE    
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.
Michael E Yeager; Dmitry D Belchenko; Cecilia M Nguyen; Kelley L Colvin; D Dunbar Ivy; K R Stenmark
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  46     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-06     Completed Date:  2012-05-03     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14-22     Citation Subset:  IM    
Division of Pulmonary, and Critical Care Medicine, Department of Pediatrics, University of Colorado at Denver, Aurora, 80138, USA.
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MeSH Terms
Activating Transcription Factor 6 / metabolism
Arteritis / metabolism*,  pathology
Cytokines / metabolism
DNA-Binding Proteins / metabolism
Endothelin-1 / genetics,  metabolism*
Hyaluronic Acid / metabolism
Hypertension, Pulmonary / genetics,  metabolism
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Monocytes / metabolism
Muscle, Smooth, Vascular / metabolism*,  pathology
Myocytes, Smooth Muscle / metabolism*,  pathology
Phosphorylation / genetics,  physiology
Pulmonary Artery / metabolism*
Receptor, Endothelin A / antagonists & inhibitors,  metabolism
Receptor, Endothelin B / metabolism
Signal Transduction / genetics,  physiology
Transcription Factors / metabolism
Unfolded Protein Response / genetics,  physiology*
Grant Support
HL-014985-35/HL/NHLBI NIH HHS; HL-084923-02/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Activating Transcription Factor 6; 0/Atf6 protein, rat; 0/Cytokines; 0/DNA-Binding Proteins; 0/Endothelin-1; 0/Receptor, Endothelin A; 0/Receptor, Endothelin B; 0/Transcription Factors; 0/regulatory factor X transcription factors; 9004-61-9/Hyaluronic Acid; EC Protein Kinase 1; EC Protein Kinase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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