| Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells. | |
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MedLine Citation:
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PMID: 20978007 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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AIMS: The mammalian silent information regulator-two 1 (Sirt1) blunts the noxious effects of cardiovascular risk factors such as type 2 diabetes mellitus and obesity. Nevertheless, the role of Sirt1 in regulating the expression of tissue factor (TF), the key trigger of coagulation, and arterial thrombus formation remains unknown. METHODS AND RESULTS: Human as well as mouse cell lines were used for in vitro experiments, and C57Bl/6 mice for in vivo procedures. Sirt1 inhibition by splitomicin or sirtinol enhanced cytokine-induced endothelial TF protein expression as well as surface activity, while TF pathway inhibitor protein expression did not change. Sirt1 inhibition further enhanced TF mRNA expression, TF promoter activity, and nuclear translocation as well as DNA binding of the p65 subunit of nuclear factor-kappa B (NFκB/p65). Sirt1 siRNA enhanced TF protein and mRNA expression, and this effect was reduced in NFκB/p65(-/-) mouse embryonic fibroblasts reconstituted with non-acetylatable Lys(310)-mutant NFκB/p65. Activation of the mitogen-activated protein kinases p38, c-Jun NH(2)-terminal kinase, and p44/42 (ERK) remained unaffected. In vivo, mice treated with the Sirt1 inhibitor splitomicin exhibited enhanced TF activity in the arterial vessel wall and accelerated carotid artery thrombus formation in a photochemical injury model. CONCLUSION: We provide pharmacological and genetic evidence that Sirt1 inhibition enhances TF expression and activity by increasing NFκB/p65 activation in human endothelial cells. Furthermore, Sirt1 inhibition induces arterial thrombus formation in vivo. Hence, modulation of Sirt1 may offer novel therapeutic options for targeting thrombosis. |
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Authors:
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Alexander Breitenstein; Sokrates Stein; Erik W Holy; Giovanni G Camici; Christine Lohmann; Alexander Akhmedov; Remo Spescha; Peter J Elliott; Christoph H Westphal; Christian M Matter; Thomas F Lüscher; Felix C Tanner |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-26 |
Journal Detail:
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Title: Cardiovascular research Volume: 89 ISSN: 1755-3245 ISO Abbreviation: Cardiovasc. Res. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0077427 Medline TA: Cardiovasc Res Country: England |
Other Details:
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Languages: eng Pagination: 464-72 Citation Subset: IM |
Affiliation:
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Cardiovascular Research, Physiology Institute, University of Zurich, 8057 Zurich, Switzerland. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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