Altered ADAMTS5 Expression and Versican Proteolysis: A Possible Molecular Mechanism in Barlow's Disease.

Autor:	Absi TS; Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Surgery, Nashville Veterans Administration, Nashville, Tennessee. Electronic address: tarek.absi@vanderbilt.edu., Galindo CL; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Gumina RJ; Department of Surgery, Nashville Veterans Administration, Nashville, Tennessee; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee., Atkinson J; Department of Pathology, Immunology, and Microbiology, Vanderbilt University Medical Center, Nashville, Tennessee., Guo Y; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee., Tomasek K; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Sawyer DB; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Byrne JG; Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee., Kaiser CA; Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Surgery, Nashville Veterans Administration, Nashville, Tennessee., Shah AS; Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee., Su YR; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Petracek M; Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Jazyk:	angličtina
Zdroj:	The Annals of thoracic surgery [Ann Thorac Surg] 2018 Apr; Vol. 105 (4), pp. 1144-1151. Date of Electronic Publication: 2017 Dec 15.
DOI:	10.1016/j.athoracsur.2017.11.035
Abstrakt:	Background: We hypothesized that gene expression profiles of mitral valve (MV) leaflets from patients with Barlow's disease (BD) are distinct from those with fibroelastic deficiency (FED). Methods: MVs were obtained from patients with BD (7 men, 3 women; 61.4 ± 12.7 years old) or FED (6 men, 5 women; 54.5 ± 6.0 years old) undergoing operations for severe mitral regurgitation (MR). Normal MVs were obtained from 6 donor hearts unmatched for transplant (3 men, 3 women; 58.3 ± 7.5 years old), and gene expression was assessed using cDNA microarrays. Select transcripts were validated by quantitative reverse-transcription polymerase chain reaction, followed by an assessment of protein levels by immunostaining. Results: The global gene expression profile for BD was clearly distinct from normal and FED groups. A total of 4,684 genes were significantly differential (fold-difference >1.5, p < 0.05) among the three groups, 1,363 of which were commonly altered in BD and FED compared with healthy individuals (eg TGFβ2 [transforming growth factor β2] and TGFβ3 were equally upregulated in BD and FED). Most interesting were 329 BD-specific genes, including ADAMTS5 (a disintegrin-like and metalloprotease domain with thrombospondin-type 5), which was uniquely downregulated in BD based on microarrays and quantitative reverse-transcription polymerase chain reaction. Consistent with this finding, the ADAMTS5 substrate versican was increased in BD and conversely lower in FED. Conclusions: MV leaflets in BD and FED exhibit distinct gene expression patterns, suggesting different pathophysiologic mechanisms are involved in leaflet remodeling. Moreover, downregulation of ADAMTS5 in BD, along with the accumulation of its substrate versican in the valvular extracellular matrix, might contribute to leaflet thickening and enlargement. (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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