title: 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) andex vivomorphometry measurement (P=0.006). TheThbs1-/-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 fromThbs1-/-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.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia.
authors.forename: Smriti Murali
authors.initials: SM
authors.lastname: Krishna
authors.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia.|National Institute of Complementary Medicine (NICM), School of Science and Health, University of Western Sydney, Campbelltown, NSW, Australia.
authors.forename: Sai Wang
authors.initials: SW
authors.lastname: Seto
authors.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia.
authors.forename: Roby
authors.initials: R
authors.lastname: Jose
authors.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia.
authors.forename: Jiaze
authors.initials: J
authors.lastname: Li
authors.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia.
authors.forename: Joseph
authors.initials: J
authors.lastname: Moxon
authors.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia.
authors.forename: Paula
authors.initials: P
authors.lastname: Clancy
authors.affiliation: Department of Physiology,Faculty of Medical and Health Sciences, Biophysics and Biophotonics Research Group, The University of Auckland, Auckland, New Zealand.
authors.forename: David J
authors.initials: DJ
authors.lastname: Crossman
authors.affiliation: School of Surgery, University of Western Australia, Perth, WA 6907, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Norman
authors.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia.|Public Health and Tropical Medicine, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Queensland 4811, Australia.
authors.forename: Theophilus I
authors.initials: TI
authors.lastname: Emeto
authors.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia jonathan.golledge@jcu.edu.au.|Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D016017:Odds Ratio; D010641:Phenotype; D059748:Proteolysis; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D019700:Thrombospondin 1 / Q000097:blood* / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014463:Ultrasonography; D066253:Vascular Remodeling
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; C439971:COL3A1 protein, human; D024061:Collagen Type III; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D019700:Thrombospondin 1; D025521:Tumor Suppressor Proteins; C000611726:thrombospondin-1, human; C585483:Thbs1 protein, mouse; D000804:Angiotensin II; D004549:Elastin; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Angiotensin II; Low density lipoprotein receptor-related protein 1; Thrombospondin-1; abdominal aortic aneurysm; extracellular matrix; maladaptive remodelling