High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency promotes angiotensin-II induced aneurysm in mice

Krishna, Smriti Murali, Seto, Sai Wang, Jose, Roby, Li, Jiaze, Moxon, Joseph, Clancy, Paula, Crossman, David J., Norman, Paul, Emeto, Theophilus I., and Golledge, Jonathan (2017) High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency promotes angiotensin-II induced aneurysm in mice. Clinical Science, 131 (12). pp. 1261-1281.

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Abstract

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 remodeling. In this study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeat 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% 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 to the relatively normal AAA neck. To further assess the role of TSP-1 in AAA 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 isolated from Thbs1-/-ApoE-/- mice showed reduced Collagen 3A1 gene expression. Furthermore, Thbs1-/-ApoE-/- mice had reduced aortic expression of low density lipoprotein receptor-related protein 1. Collectively, findings from this study suggest that TSP-1 deficiency promotes maladaptive remodeling of the extracellular matrix leading to accelerated AAA progression.

Item ID: 48840
Item Type: Article (Refereed Research - C1)
Keywords: thrombospondin-1, abdominal aortic aneurysm, angiotensin II, extracellular matrix, collagen, maladaptive remodelling, matrix metalloproteinase, low density lipoprotein receptor-related protein 1
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© The Authors. Use of open access articles is permitted based on the terms of the specific Creative Commons Licence under which the article is published. CC BY NC-ND.

ISSN: 1470-8736
Funders: National Health and Medical Research Council (NHMRC), Queensland Government
Projects and Grants: NHMRC 1000967, 540404, 1021416, 1079193, 1079369, 1098717 & 1117061
Date Deposited: 03 May 2017 03:35
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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