Modulation of thrombomodulin-dependent activation of human protein C through differential expression of endothelial Smads

George Sandusky, David T. Berg, Mark A. Richardson, Laura Myers, Brian W. Grinnell

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Protein C is a plasma protease that in its active form plays a central role in the regulation of vascular function by modulating thrombosis, inflammation, and apoptosis. A central player in this pathway is the cytokine-regulated receptor thrombomodulin (TM), which functions as a co-factor for the thrombin-dependent generation of activated protein C. We have found that tumor necrosis factor-β (TGF-β)-dependent suppression of TM on endothelial cells is differentially regulated by endothelial Smad6s and Smad7. Overexpression of Smad6s resulted in activation of a TGF-β reporter alone and enhanced TGF-β response. Moreover, Smad6s overexpression suppressed TM and subsequently reduced activated protein C generation. Antisense inhibition of Smad6s expression enhanced the TM-dependent activation of protein C, whereas blocking the inhibitory Smad7 by antisense resulted in reduced TM-dependent activation of protein C. The effect of Smad6s appeared to be due, at least in part, to up-regulation of TGF-β itself. Immunohistochemisty studies in normal versus atherosclerotic vessels showed that TM levels were suppressed in the endothelium over plaque. Consistent with the in vitro data, we found differential expression of Smad6s and Smad7 in normal versus atherosclerotic vessels, with Smad6s expression low in normal vessels but elevated in atherosclerotic vessels. In contrast, the opposite expression pattern was observed for Smad7. Overall, our results suggest that the relative balance of these intracellular Smads modulate the balance of endothelial function with regard to protein C activation.

Original languageEnglish (US)
Pages (from-to)49815-49819
Number of pages5
JournalJournal of Biological Chemistry
Volume277
Issue number51
DOIs
StatePublished - Dec 20 2002
Externally publishedYes

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Thrombomodulin
Protein C
Chemical activation
Modulation
Cytokine Receptors
Endothelial cells
Thrombin
Endothelium
Blood Vessels
Thrombosis
Peptide Hydrolases
Up-Regulation
Endothelial Cells
Tumor Necrosis Factor-alpha
Apoptosis
Cytokines
Inflammation
Plasmas

ASJC Scopus subject areas

  • Biochemistry

Cite this

Modulation of thrombomodulin-dependent activation of human protein C through differential expression of endothelial Smads. / Sandusky, George; Berg, David T.; Richardson, Mark A.; Myers, Laura; Grinnell, Brian W.

In: Journal of Biological Chemistry, Vol. 277, No. 51, 20.12.2002, p. 49815-49819.

Research output: Contribution to journalArticle

Sandusky, George ; Berg, David T. ; Richardson, Mark A. ; Myers, Laura ; Grinnell, Brian W. / Modulation of thrombomodulin-dependent activation of human protein C through differential expression of endothelial Smads. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 51. pp. 49815-49819.
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