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.

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 (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.

• Authors: Smriti Murali Krishna, Sai Wang Seto, Roby Jose, Jiaze Li, Joseph Moxon, Paula Clancy, David J Crossman, Paul Norman, Theophilus I Emeto, Jonathan Golledge
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 131 Issue 12 Pg. 1261-1281 (Jun 01 2017) ISSN: 1470-8736 [Electronic] England
• PMID: 28364044 (Publication Type: Journal Article)
• Copyright: © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Apolipoproteins E
• Biomarkers
• COL3A1 protein, human
• Collagen Type III
• Low Density Lipoprotein Receptor-Related Protein-1
• Lrp1 protein, mouse
• Receptors, LDL
• Thrombospondin 1
• Tumor Suppressor Proteins
• thrombospondin-1, human
• thrombospondin-1, mouse
• Angiotensin II
• Elastin
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Angiotensin II
• Animals
• Aorta, Abdominal (diagnostic imaging, metabolism, pathology)
• Aortic Aneurysm, Abdominal (blood, chemically induced, metabolism, prevention & control)
• Apolipoproteins E (deficiency, genetics)
• Biomarkers (blood)
• Cells, Cultured
• Collagen Type III (genetics, metabolism)
• Disease Models, Animal
• Disease Progression
• Elastin (metabolism)
• Genetic Predisposition to Disease
• Humans
• Low Density Lipoprotein Receptor-Related Protein-1
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice, Knockout
• Odds Ratio
• Phenotype
• Proteolysis
• Receptors, LDL (genetics, metabolism)
• Risk Factors
• Thrombospondin 1 (blood, deficiency, genetics)
• Time Factors
• Tumor Suppressor Proteins (genetics, metabolism)
• Ultrasonography
• Vascular Remodeling