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Endothelin-1 stimulation of proteoglycan synthesis in vascular smooth muscle is mediated by endothelin receptor transactivation of the transforming growth factor-[beta] type I receptor
- Source :
- Journal of cardiovascular pharmacology. 56(4)
- Publication Year :
- 2010
-
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)-[beta] receptor, T[beta]RI. 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 T[beta]RI 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-[beta] (T[beta]RI). 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-[beta] receptor activation.
- Subjects :
- Endothelin Receptor Antagonists
Transcriptional Activation
medicine.medical_specialty
Endothelin receptor type A
Myocytes, Smooth Muscle
Receptor, Transforming Growth Factor-beta Type I
Dioxoles
Biology
Protein Serine-Threonine Kinases
Muscle, Smooth, Vascular
Growth factor receptor
Internal medicine
medicine
Enzyme-linked receptor
Humans
Phosphorylation
Protease-activated receptor 2
Cells, Cultured
Insulin-like growth factor 1 receptor
Glycosaminoglycans
Pharmacology
Sulfonamides
Endothelin-1
Endothelin receptor antagonist
Receptors, Endothelin
Receptor transactivation
Bosentan
Cell biology
Endocrinology
Interleukin-21 receptor
Benzamides
Proteoglycans
Cardiology and Cardiovascular Medicine
Receptors, Transforming Growth Factor beta
Subjects
Details
- ISSN :
- 15334023
- Volume :
- 56
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Journal of cardiovascular pharmacology
- Accession number :
- edsair.doi.dedup.....80eb22215628cc1db78789b3133f27db