| Protein phosphatase 2B inhibition promotes the secretion of von Willebrand factor from endothelial cells. | |
| | |
MedLine Citation:
|
PMID: 19344364 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
BACKGROUND: Secretion of Weibel-Palade body (WPB) contents is regulated, in part, by the phosphorylation of proteins that constitute the endothelial exocytotic machinery. In comparison to protein kinases, a role for protein phosphatases in regulating endothelial exocytosis is undefined. OBJECTIVE AND METHOD: In this study, we investigated the role of protein phosphatase 2B (PP2B) in the process of endothelial exocytosis using pharmacological and gene knockdown approaches. RESULTS: We show that inhibition of protein phosphatase 2B (PP2B) activity by cyclosporine A (CsA), tacrolimus or a cell-permeable PP2B autoinhibitory peptide promotes the secretion of ultralarge von Willebrand factor (ULVWF) from human umbilical vein endothelial cells (HUVECs) in the absence of any other endothelial cell-stimulating agent. PP2B inhibitor-induced secretion and anchorage of ULVWF strings from HUVECs mediate platelet tethering. In support of a role for PP2B in von Willebrand factor (VWF) secretion, the catalytic subunit of PP2B interacts with the vesicle trafficking protein, Munc18c. Serine phosphorylation of Munc18c, which promotes granule exocytosis in other secretory cells, is increased in CsA-treated HUVECs, suggesting that this process may be involved in CsA-mediated WPB exocytosis. Furthermore, the plasma VWF antigen level is also enhanced in CsA-treated mice, and small interfering RNA-mediated knockdown of the alpha and beta isoforms of the PP2B-A subunit in HUVECs enhanced VWF secretion. CONCLUSIONS: These observations suggest that CsA promotes VWF release, in part by inhibition of PP2B activity, and are compatible with the clinically observed association of CsA treatment and increased plasma VWF levels in humans. |
| | |
Authors:
|
L H Nolasco; F C Gushiken; N A Turner; T S Khatlani; S Pradhan; J-F Dong; J L Moake; K V Vijayan |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-03-27 |
Journal Detail:
|
Title: Journal of thrombosis and haemostasis : JTH Volume: 7 ISSN: 1538-7836 ISO Abbreviation: J. Thromb. Haemost. Publication Date: 2009 Jun |
Date Detail:
|
Created Date: 2009-06-24 Completed Date: 2009-09-15 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 101170508 Medline TA: J Thromb Haemost Country: England |
Other Details:
|
Languages: eng Pagination: 1009-18 Citation Subset: IM |
Affiliation:
|
Department of Bioengineering, Rice University, Houston, TX 77030, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Base Sequence Calcineurin / antagonists & inhibitors*, genetics Cells, Cultured DNA Primers Endothelium, Vascular / cytology, secretion* Enzyme Inhibitors / pharmacology Humans Mice Mice, Inbred BALB C RNA, Messenger / genetics Reverse Transcriptase Polymerase Chain Reaction von Willebrand Factor / secretion* |
| Grant Support | |
ID/Acronym/Agency:
|
HL071895/HL/NHLBI NIH HHS; HL081613/HL/NHLBI NIH HHS; T-32HL072754/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/DNA Primers; 0/Enzyme Inhibitors; 0/RNA, Messenger; 0/von Willebrand Factor; EC 3.1.3.16/Calcineurin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Effect of time of admission on compliance with deep vein thrombosis prophylaxis in a tertiary medica...
Next Document: Cerebral Atrophy in Cerebrovascular Disorders.