Show simple item record

dc.contributor.authorOsman, Narin
Grande-Allen, K. Jane
Ballinger, Mandy L.
Getachew, Robel
Marasco, Silvana
O'Brien, Kevin D.
Little, Peter J.
dc.date.accessioned 2015-07-09T20:14:49Z
dc.date.available 2015-07-09T20:14:49Z
dc.date.issued 2013
dc.identifier.citation Osman, Narin, Grande-Allen, K. Jane, Ballinger, Mandy L., et al.. "Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans." Cardiovascular Pathology, 22, no. 2 (2013) Elsevier: 146-155. http://dx.doi.org/10.1016/j.carpath.2012.07.002.
dc.identifier.urihttps://hdl.handle.net/1911/80866
dc.description.abstract Objective: Calcific aortic valve disease is a progressive condition that shares some common pathogenic features with atherosclerosis. Transforming growth factor-β1 is a recognized mediator of atherosclerosis and is expressed in aortic valve lesions. Transforming growth factorβ1 stimulates glycosaminoglycan elongation of proteoglycans that is associated with increased lipid binding. We investigated the presence of transforming growth factor-β1 and downstream signaling intermediates in diseased human aortic valves and the effects of activated transforming growth factor-β1 receptor signaling on aortic valve interstitial cell proteoglycan synthesis and lipid binding as a possible mechanism for the initiation of the early lesion of calcific aortic valve disease. Methods and results: Diseased human aortic valve leaflets demonstrated strong immunohistochemical staining for transforming growth factor-β1 and phosphorylated Smad2/3. In primary porcine aortic valve interstitial cells, Western blots showed that transforming growth factor-β1 stimulated phosphorylation in both the carboxy and linker regions of Smad2/3, which was inhibited by the transforming growth factor-β1 receptor inhibitor SB431542. Gel electrophoresis and size exclusion chromatography demonstrated that SB431542 decreased transforming growth factor-β1-mediated [35S]-sulfate incorporation into proteoglycans in a dose-dependent manner. Further, in proteoglycans derived from transforming growth factor-β1-treated valve interstitial cells, gel mobility shift assays demonstrated that inhibition of transforming growth factor-β1 receptor signaling resulted in decreased lipid binding. Conclusions: Classic transforming growth factor-β1 signaling is present in human aortic valves in vivo and contributes to the modification of proteoglycans expressed by valve interstitial cells in vitro. These findings suggest that transforming growth factor-β1 may promote increased low-density lipoprotein binding in the early phases of calcific aortic valve disease.
dc.language.iso eng
dc.publisher Elsevier
dc.rights This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier.
dc.title Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans
dc.type Journal article
dc.citation.journalTitle Cardiovascular Pathology
dc.subject.keywordheart valves
Smad
transforming growth factor-?
lipids
glycosaminoglycans
dc.citation.volumeNumber 22
dc.citation.issueNumber 2
dc.type.dcmi Text
dc.identifier.doihttp://dx.doi.org/10.1016/j.carpath.2012.07.002
dc.identifier.pmid 22999704
dc.type.publication post-print
dc.citation.firstpage 146
dc.citation.lastpage 155


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record