Document Detail


Arsenic activates endothelin-1 Gi protein-coupled receptor signaling to inhibit stem cell differentiation in adipogenesis.
MedLine Citation:
PMID:  23152186     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Dysfunctional lipid and glucose metabolism contribute to metabolic syndrome-a major public health concern that enhances cardiovascular disease risk. Arsenic (As(III)) exposure may increase metabolic syndrome and cardiovascular disease risk by impairing adipose tissue differentiation, function, and insulin sensitivity through pathogenic mechanisms that remain unclear. We hypothesized that As(III) signals through the Pertussis toxin (Ptx) sensitive, Gi protein-coupled receptor (GPCR) to impair adipogenesis, as previously demonstrated for its stimulation of vascular oxidant generation, angiogenesis, and remodeling. Because both As(III) and GPCR ligands inhibit progenitor cell differentiation into adipocytes, we investigated the hypothesis in a model of low-passage human mesenchymal stem cells (hMSC). As(III) (0.1-1.0 µM) suppressed dexamethasone/insulin-induced hMSC adipogenesis, as indicated by decreased transcriptional promoters of differentiation, decreased fat droplet formation, and decreased expression of differentiated adipocyte markers, such as adiponectin and perilipin. Preincubating hMSC with Ptx prevented 90% of the suppressive effect of As(III). Selective competitive antagonists of Gi-coupled endothelin-1 type A and B receptors were ~60% effective in blocking As(III) inhibition and combination of antagonists to both receptors were 85% effective. In contrast, antagonists to the sphingosine-1-phosphate type 1 receptor (previously shown to mediate As(III) vascular effects) or the angiotensin II type 1 receptor were ineffective in blocking As(III) effects. These studies suggest a majority of arsenic-inhibited adipocyte differentiation, and metabolism requires endothelin-1 GPCRs and that As(III) effects on GPCR signaling are tissue and context specific. This may represent a significant mechanism for the contribution of arsenic exposure to increased metabolic and cardiovascular diseases.
Authors:
Linda R Klei; D Yesica Garciafigueroa; Aaron Barchowsky
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-14
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  131     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-23     Completed Date:  2013-08-12     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  512-20     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adipogenesis*
Animals
Arsenic / pharmacology*
Blotting, Western
Cell Differentiation*
Cells, Cultured
Endothelin-1 / metabolism*
GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
Humans
Mice
Polymerase Chain Reaction
Protein Binding
Receptors, G-Protein-Coupled / metabolism*
Signal Transduction*
Stem Cells / cytology*
Grant Support
ID/Acronym/Agency:
R01ES013781/ES/NIEHS NIH HHS; R01ES013781-S1/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Endothelin-1; 0/Receptors, G-Protein-Coupled; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gi-Go; N712M78A8G/Arsenic
Comments/Corrections

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