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152 The role of adamts-5 in extracellular matrix remodelling of thoracic aortic aneurysms
  1. Marika Fava1,
  2. Javier Barallobre-Barreiro1,
  3. Ferheen Baig1,
  4. Ursula Mayr1,
  5. Marc Lynch1,
  6. Abhishek Joshi1,
  7. Norman Catibog1,
  8. Renata Gomes1,
  9. Temo Barwari1,
  10. Pouya Youssefi2,
  11. Alessandro Viviano2,
  12. Xiaoke Yin1,
  13. Marjan Jahangiri2,
  14. Manuel Mayr1
  1. 1King’s College London
  2. 2St. Georges Hospital, University of London

Abstract

ADAMTS, aneurysm, ECM

Introduction Thoracic aortic aneurysms (TAA) are common in patients with bicuspid aortic valve (BAV). ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs) has recently been implicated in TAA formation (Oller et al, Nat Med, 2017). The contribution of other ADAMTS proteases to TAA is currently unknown.

Method Using proteomics, we compared the extracellular matrix (ECM) composition in the greater (i.e. the aneurysm-prone area) and lesser curvatures of TAA in BAV patients. Our findings in patients were complemented by studies in ADAMTS-5 deficient mice.

Results In BAV patients with TAA, the large aggregating proteoglycan versican was the most differentially regulated ECM protein in the aneurysm-prone area. In mice, ADAMTS-5 is the main versican-degrading member of the ADAMTS family. Hence, a model of aortic dilatation by angiotensin II (AngII) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts-5cd). AngII treatment raised blood pressure in wild-type (WT) mice; this response was attenuated and associated with increased dilation of the ascending aorta in Adamts-5cd mice. Concomitantly, versican accumulation and reduced versican degradation products were observed in Adamts-5cd aortas compared to WT controls. The presence of other ADAMTS members, including ADAMTS-1, was not sufficient to maintain versican processing and prevent aortic dilation in Adamts-5cd mice.

Conclusion Our results support the emerging role of ADAMTS proteases in TAA. ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. Further studies are needed to define the ECM substrates of the different ADAMTS proteases and their contribution to TAA formation.

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