Endothelin-1 stimulation of proteoglycan synthesis in vascular smooth muscle is mediated by endothelin receptor transactivation of the transforming growth factor-β type I receptor

Little, Peter J., Burch, Micah L., Getachew, Robel, Al-aryahi, Sefaa and Osman, Narin (2010) Endothelin-1 stimulation of proteoglycan synthesis in vascular smooth muscle is mediated by endothelin receptor transactivation of the transforming growth factor-β type I receptor. Journal of Cardiovascular Pharmacology, 56 4: 360-368. doi:10.1097/FJC.0b013e3181ee6811


Author Little, Peter J.
Burch, Micah L.
Getachew, Robel
Al-aryahi, Sefaa
Osman, Narin
Title Endothelin-1 stimulation of proteoglycan synthesis in vascular smooth muscle is mediated by endothelin receptor transactivation of the transforming growth factor-β type I receptor
Journal name Journal of Cardiovascular Pharmacology   Check publisher's open access policy
ISSN 0160-2446
1533-4023
Publication date 2010-10-01
Sub-type Article (original research)
DOI 10.1097/FJC.0b013e3181ee6811
Open Access Status Not Open Access
Volume 56
Issue 4
Start page 360
End page 368
Total pages 9
Place of publication Philadelphia, PA United States
Publisher Lippincott Williams & Wilkins
Language eng
Formatted abstract
We utilized human vascular smooth muscle cells to address the question if a G-protein-coupled receptor, the endothelin (ET) receptor, could transactivate a serine/threonine kinase receptor, specifically the transforming growth factor (TGF)-β receptor, TβRI. Functionality of the interaction was addressed by studying endothelin-1-stimulated proteoglycan synthesis. Signaling molecules were assessed by Western blotting and proteoglycan synthesis by [ 35S]sulfate and 35S-met/cys incorporation and molecular size by SDS-PAGE. Endothelin-1 treatment led to a time- and concentration- dependent increase in cytosolic phosphoSmad2C, which was inhibited by the mixed endothelin receptor antagonist bosentan and the TβRI antagonist SB431542. Endothelin-1 treatment led to a time-dependent increase in nuclear phosphoSmad2C. Endothelin-1-stimulated proteoglycan synthesis was partially inhibited (40%) by SB431542 and completely blocked by bosentan. The effect of endothelin-1 to stimulate an increase in glycosaminoglycan size on biglycan was also blocked in a concentration-dependent manner by SB431542. These data extend the current paradigm of G-protein coupled receptor signaling to include the transactivation of the serine kinase receptor for TGF-β (TβRI). This response should be considered in the context of response to endothelin-1, and the options for therapeutically targeting endothelin-1 are accordingly broadened to include downstream signaling otherwise associated with TGF-β receptor activation.
Keyword Endothelin receptors
Glycosaminoglycans
Proteoglycans
Receptor transactivation
Receptors
Transforming growth factor β
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Pharmacy Publications
 
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