Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearman’s rho −0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19–0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1−/−ApoE−/−, n=20) and control mice (ApoE−/−, n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1−/− ApoE−/− mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1−/−ApoE−/− mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1−/−ApoE−/− mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1−/−ApoE−/− mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression.
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The accompanying caption is: Image demonstrates a 3D reconstruction of the neurovascular unit in a hippocampal artery in the mouse brain. For further details, see article by Nizari et al in this issue, pages 1207-1214. Image kindly provided by Cheryl Hawkes.
Research Article|
June 07 2017
High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice
Smriti Murali Krishna;
Smriti Murali Krishna
1The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
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Sai Wang Seto;
Sai Wang Seto
1The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
2National Institute of Complementary Medicine (NICM), School of Science and Health, University of Western Sydney, Campbelltown, NSW, Australia
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Roby Jose;
Roby Jose
1The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
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Jiaze Li;
Jiaze Li
1The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
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Joseph Moxon;
Joseph Moxon
1The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
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Paula Clancy;
Paula Clancy
1The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
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David J. Crossman;
David J. Crossman
3Department of Physiology,Faculty of Medical and Health Sciences, Biophysics and Biophotonics Research Group, The University of Auckland, Auckland, New Zealand
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Paul Norman;
Paul Norman
4School of Surgery, University of Western Australia, Perth, WA 6907, Australia
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Theophilus I. Emeto;
Theophilus I. Emeto
1The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
5Public Health and Tropical Medicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Queensland 4811, Australia
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Jonathan Golledge
1The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
6Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Australia
Correspondence: Jonathan Golledge ([email protected])
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Publisher: Portland Press Ltd
Received:
December 15 2016
Revision Received:
March 23 2017
Accepted:
March 31 2017
Accepted Manuscript online:
March 31 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (12): 1261–1281.
Article history
Received:
December 15 2016
Revision Received:
March 23 2017
Accepted:
March 31 2017
Accepted Manuscript online:
March 31 2017
Connected Content
A commentary has been published:
Thrombospondin-1 contributes to slower aortic aneurysm growth by inhibiting maladaptive remodeling of extracellular matrix
Citation
Smriti Murali Krishna, Sai Wang Seto, Roby Jose, Jiaze Li, Joseph Moxon, Paula Clancy, David J. Crossman, Paul Norman, Theophilus I. Emeto, Jonathan Golledge; High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice. Clin Sci (Lond) 1 June 2017; 131 (12): 1261–1281. doi: https://doi.org/10.1042/CS20160970
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