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

Tarek S. Absi, Cristi L. Galindo, Richard J. Gumina, James Atkinson, Yan Guo, Kelsey Tomasek, Douglas B. Sawyer, John G. Byrne, Clayton A. Kaiser, Ashish S. Shah, Yan Ru Su, Michael Petracek

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1144-1151
Number of pages8
JournalAnnals of Thoracic Surgery
Volume105
Issue number4
DOIs
StatePublished - Apr 2018

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Cartilage Oligomeric Matrix Protein
Versicans
Disintegrins
Metalloproteases
Proteolysis
Deficiency Diseases
Mitral Valve
Transcriptome
Reverse Transcription
Down-Regulation
Gene Expression
Polymerase Chain Reaction
Mitral Valve Insufficiency
Transforming Growth Factors
Oligonucleotide Array Sequence Analysis
Genes
Extracellular Matrix
Tissue Donors
Transplants

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Absi, T. S., Galindo, C. L., Gumina, R. J., Atkinson, J., Guo, Y., Tomasek, K., ... Petracek, M. (2018). Altered ADAMTS5 Expression and Versican Proteolysis: A Possible Molecular Mechanism in Barlow's Disease. Annals of Thoracic Surgery, 105(4), 1144-1151. https://doi.org/10.1016/j.athoracsur.2017.11.035

Altered ADAMTS5 Expression and Versican Proteolysis : A Possible Molecular Mechanism in Barlow's Disease. / Absi, Tarek S.; Galindo, Cristi L.; Gumina, Richard J.; Atkinson, James; Guo, Yan; Tomasek, Kelsey; Sawyer, Douglas B.; Byrne, John G.; Kaiser, Clayton A.; Shah, Ashish S.; Su, Yan Ru; Petracek, Michael.

In: Annals of Thoracic Surgery, Vol. 105, No. 4, 04.2018, p. 1144-1151.

Research output: Contribution to journalArticle

Absi, TS, Galindo, CL, Gumina, RJ, Atkinson, J, Guo, Y, Tomasek, K, Sawyer, DB, Byrne, JG, Kaiser, CA, Shah, AS, Su, YR & Petracek, M 2018, 'Altered ADAMTS5 Expression and Versican Proteolysis: A Possible Molecular Mechanism in Barlow's Disease', Annals of Thoracic Surgery, vol. 105, no. 4, pp. 1144-1151. https://doi.org/10.1016/j.athoracsur.2017.11.035
Absi, Tarek S. ; Galindo, Cristi L. ; Gumina, Richard J. ; Atkinson, James ; Guo, Yan ; Tomasek, Kelsey ; Sawyer, Douglas B. ; Byrne, John G. ; Kaiser, Clayton A. ; Shah, Ashish S. ; Su, Yan Ru ; Petracek, Michael. / Altered ADAMTS5 Expression and Versican Proteolysis : A Possible Molecular Mechanism in Barlow's Disease. In: Annals of Thoracic Surgery. 2018 ; Vol. 105, No. 4. pp. 1144-1151.
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abstract = "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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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

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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