Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Osman, Narin, Grande-Allen, K. Jane, Ballinger, Mandy L., Getachew, Robel, Marasco, Silvana, O'Brien, Kevin D. and Little, Peter J. (2013) Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans. Cardiovascular Pathology, 22 2: 146-155. doi:10.1016/j.carpath.2012.07.002


Author Osman, Narin
Grande-Allen, K. Jane
Ballinger, Mandy L.
Getachew, Robel
Marasco, Silvana
O'Brien, Kevin D.
Little, Peter J.
Title Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans
Journal name Cardiovascular Pathology   Check publisher's open access policy
ISSN 1054-8807
1879-1336
Publication date 2013-03-01
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.carpath.2012.07.002
Open Access Status Not Open Access
Volume 22
Issue 2
Start page 146
End page 155
Total pages 10
Place of publication Philadelphia, PA United States
Publisher Elsevier
Language eng
Formatted 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.
Keyword Heart valves
Smad
Transforming growth factor-β
Lipids
Glycosaminoglycans
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Pharmacy Publications
 
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