TY - JOUR
T1 - Altered ADAMTS5 Expression and Versican Proteolysis
T2 - A Possible Molecular Mechanism in Barlow's Disease
AU - Absi, Tarek S.
AU - Galindo, Cristi L.
AU - Gumina, Richard J.
AU - Atkinson, James
AU - Guo, Yan
AU - Tomasek, Kelsey
AU - Sawyer, Douglas B.
AU - Byrne, John G.
AU - Kaiser, Clayton A.
AU - Shah, Ashish S.
AU - Su, Yan Ru
AU - Petracek, Michael
N1 - Funding Information:
This work was supported in part by the Vanderbilt Clinical and Translational Science Award ( UL1-RR-024975 ) and the National Institutes of Health ( K01-HL-121045 , and U01-HL-100398 ). The authors wish to thank Li Wang for her technical assistance on immunohistochemistry data analysis.
Publisher Copyright:
© 2018 The Society of Thoracic Surgeons
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.athoracsur.2017.11.035
DO - 10.1016/j.athoracsur.2017.11.035
M3 - Article
C2 - 29248417
AN - SCOPUS:85044151423
SN - 0003-4975
VL - 105
SP - 1144
EP - 1151
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
IS - 4
ER -