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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    • "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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    • "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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