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Original Research
Open Access

Role of ADAMTS (A Disintegrin and Metalloproteinase With Thrombospondin Motifs)-5 in Aortic Dilatation and Extracellular Matrix Remodeling

Marika Fava, Javier Barallobre-Barreiro, Ursula Mayr, Ruifang Lu, Athanasios Didangelos, Ferheen Baig, Marc Lynch, Norman Catibog, Abhishek Joshi, Temo Barwari, Xiaoke Yin, Marjan Jahangiri, Manuel Mayr
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https://doi.org/10.1161/ATVBAHA.117.310562
Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;ATVBAHA.117.310562
Originally published April 5, 2018
Marika Fava
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Javier Barallobre-Barreiro
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Ursula Mayr
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Ruifang Lu
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Athanasios Didangelos
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Ferheen Baig
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Marc Lynch
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Norman Catibog
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Abhishek Joshi
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Temo Barwari
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Xiaoke Yin
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Marjan Jahangiri
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Manuel Mayr
From the King’s British Heart Foundation Centre, King’s College London, United Kingdom (M.F., J.B.-B., U.M., R.L., A.D., F.B., M.L., N.C., A.J., T.B., X.Y., M.M.); St George’s University of London, NHS Trust, United Kingdom (M.F., M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, NY (M.F., M.M.).
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Abstract

Objective—Thoracic aortic aneurysm (TAA), a degenerative disease of the aortic wall, is accompanied by changes in the structure and composition of the aortic ECM (extracellular matrix). The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteases has recently been implicated in TAA formation. This study aimed to investigate the contribution of ADAMTS-5 to TAA development.

Approach and Results—A model of aortic dilatation by AngII (angiotensin II) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts5Δcat). Adamts5Δcat mice showed an attenuated rise in blood pressure while displaying increased dilatation of the ascending aorta (AsAo). Interestingly, a comparison of the aortic ECM from AngII-treated wild-type and Adamts5Δcat mice revealed versican as the most upregulated ECM protein in Adamts5Δcat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine) and a decrease of LRP1 (low-density lipoprotein-related protein 1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS5, attenuated the generation of versikine, but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5Δcat mice but was not sufficient to maintain versican processing and prevent aortic dilatation.

Conclusions—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.

  • aneurysm
  • blood pressure
  • extracellular matrix
  • mice
  • thrombospondin
  • Received December 22, 2017.
  • Accepted March 19, 2018.
  • © 2018 The Authors.

Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

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    Role of ADAMTS (A Disintegrin and Metalloproteinase With Thrombospondin Motifs)-5 in Aortic Dilatation and Extracellular Matrix Remodeling
    Marika Fava, Javier Barallobre-Barreiro, Ursula Mayr, Ruifang Lu, Athanasios Didangelos, Ferheen Baig, Marc Lynch, Norman Catibog, Abhishek Joshi, Temo Barwari, Xiaoke Yin, Marjan Jahangiri and Manuel Mayr
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;ATVBAHA.117.310562, originally published April 5, 2018
    https://doi.org/10.1161/ATVBAHA.117.310562

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    Role of ADAMTS (A Disintegrin and Metalloproteinase With Thrombospondin Motifs)-5 in Aortic Dilatation and Extracellular Matrix Remodeling
    Marika Fava, Javier Barallobre-Barreiro, Ursula Mayr, Ruifang Lu, Athanasios Didangelos, Ferheen Baig, Marc Lynch, Norman Catibog, Abhishek Joshi, Temo Barwari, Xiaoke Yin, Marjan Jahangiri and Manuel Mayr
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;ATVBAHA.117.310562, originally published April 5, 2018
    https://doi.org/10.1161/ATVBAHA.117.310562
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