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HERO ID
975862
Reference Type
Journal Article
Subtype
Abstract
Title
The peroxynitrite generator 3-morpholino-sydnonimine (SIN-1) nitrates Hsp90 and is associated with its reduced acetylation and increased interaction with vascular endothelial growth factor receptor-2
Author(s)
Chatterjee, A; Smith, A; Catravas, JD; Black, SM
Year
2008
Is Peer Reviewed?
Yes
Journal
Free Radical Biology and Medicine
ISSN:
0891-5849
EISSN:
1873-4596
Volume
45
Issue
Suppl.
Page Numbers
S44-S44
Language
English
Web of Science Id
WOS:000260867900120
URL
http://www.sciencedirect.com/science/article/pii/S0891584908006217
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3452652
SFRBM's 15th Annual Meeting: Program and Abstracts
Abstract
Heat shock protein 90 (hsp90), a ubiquitous molecular chaperone, assists in proper folding, maturation, and enzymatic activity of numerous client proteins. We have previously shown that hsp90 plays a deleterious role in sepsis-induced acute lung injury (ALI). However, the molecular mechanism by which hsp90 exerts this detrimental effect has not been adequately resolved. Histone deacetylase-6 (HDAC6) can bind to hsp90 and by deacetylating specific lysine residues can strengthen the association of hsp90 with its client proteins. Certain hsp90 client proteins are thought to play a pro-inflammatory role in ALI. for example, vascular endothelial growth factor receptor-2 (VEGFR-2) is known to cause endothelial barrier dysfunction through its activation by VEGF. Sepsis-induced ALI is associated with endothelial barrier dysfunction and increased synthesis of reactive nitrogen species, such as peroxynitrite, which can modify a variety of proteins altering their function. Here we investigate the in vitro effect of the peroxynitrite generator, SIN-1 on hsp90-VEGFR-2 protein interactions. We found that in bovine aortic endothelial cells (BAEC), SIN-1 (500μM, 2h) significantly increased hsp90 nitration (2.7± 0.55-fold, P<0.05 vs. control) and its association with VEGFR-2 (+1.23 ± 0.06-fold, P<0.05 vs. control). Treatment of BAEC with SIN-1 also significantly increased VEGFR-2 protein levels. Further, we observed a significant increase in hsp90 association with HDAC6 (1.6± 0.10-fold, P<0.05 vs. control) together with a reduction in hsp90 acetylation (0.76± 0.2-fold, P<0.05 vs. control). Utilizing an in vivo model of sepsis-induced lung injury, we observed a significant increase in lung hsp90 nitration and hsp90-VEGFR2 association, 4 hr post ip injection of bacterial endotoxin (P<0.05 vs saline control). We conclude that nitration of hsp90 may serve as an important pathologic event that results in proper maturation and folding of VEGFR-2, and represents a potential mechanism for the pulmonary vascular leak seen in sepsis.
Conference Name
Society for Free Radical Biology and Medicine 15th Annual Meeting
Conference Location
Indianapolis, IN
Conference Dates
November 19-23, 2008
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