Adamts5 -/- mice exhibit altered aggrecan proteolytic profiles that correlate with ascending aortic anomalies

Research output: Contribution to journalArticle

Authors

  • Loren E. Dupuis
  • E. Lockett Nelson
  • Brittany Hozik
  • Sarah C. Porto
  • Alexandra Rogers-Decotes
  • Amanda Fosang
  • Christine B. Kern

External Institution(s)

  • Medical University of South Carolina
  • University of Melbourne

Details

Original languageEnglish (US)
Pages (from-to)2067-2081
Number of pages15
JournalArteriosclerosis, thrombosis, and vascular biology
Volume39
Issue number10
StatusPublished - Oct 1 2019
Peer-reviewedYes

Abstract

Objective: Investigate the requirement of Aggrecan (Acan) cleavage during aortic wall development in a murine model with ADAMTS (a disintegrin-like and metalloprotease domain with thrombospondin-type motifs) 5 deficiency and bicuspid aortic valves. Approach: Mice with altered extracellular matrix remodeling of proteoglycans will be examined for anomalies in ascending aortic wall development. Neo-epitope antibodies that recognize ADAMTS cleaved Acan fragments will be used to investigate the mechanistic requirement of Acan turnover, in aortic wall development. Results: Adamts5-/-;Smad2+/- mice exhibited a high penetrance of aortic anomalies (n=17/17); Adamts5-/-;Smad2+/- mice with bicuspid aortic valves (7/17) showed a higher number of anomalies than Adamts5-/-;Smad2+/- mice with tricuspid aortic valves. Single mutant Adamts5-/- mice also displayed a high penetrance of aortic anomalies (n=19/19) compared with wild type (n=1/11). Aortic anomalies correlated with Acan accumulation that was apparent at the onset of elastogenesis in Adamts5-/- mice. Neo-epitope antibodies that recognize the initial amino acids in the Acan cleaved fragments neo-FREEE, neo-GLGS, and neo-SSELE were increased in the Adamts5-/- aortas compared with WT. Conversely, neo-TEGE, which recognizes highly digested Acan core fragments, was reduced in Adamts5-/- mice. However, mice containing a mutation in the TEGE373374ALGSV site, rendering it noncleavable, had low penetrance of aortic anomalies (n=2/4). Acan neo-DIPEN and neo-FFGVG fragments were observed in the aortic adventitia; Acan neo-FFGVG was increased abnormally in the medial layer and overlapped with smooth muscle cell loss in Adamts5-/- aortas. Conclusions: Disruption of ADAMTS5 Acan cleavage during development correlates with ascending aortic anomalies. These data indicate that the mechanism of ADAMTS5 Acan cleavage may be critical for normal aortic wall development.

    Research areas

  • Aggrecans, Animals, Aorta, Bicuspid, Extracellular matrix, Mice, Protease

Citation formats

APA

Dupuis, L. E., Nelson, E. L., Hozik, B., Porto, S. C., Rogers-Decotes, A., Fosang, A., & Kern, C. B. (2019). Adamts5 -/- mice exhibit altered aggrecan proteolytic profiles that correlate with ascending aortic anomalies. Arteriosclerosis, thrombosis, and vascular biology, 39(10), 2067-2081. https://doi.org/10.1161/ATVBAHA.119.313077

Harvard

Dupuis, LE, Nelson, EL, Hozik, B, Porto, SC, Rogers-Decotes, A, Fosang, A & Kern, CB 2019, 'Adamts5 -/- mice exhibit altered aggrecan proteolytic profiles that correlate with ascending aortic anomalies', Arteriosclerosis, thrombosis, and vascular biology, vol. 39, no. 10, pp. 2067-2081. https://doi.org/10.1161/ATVBAHA.119.313077