title: Increased ADAMTS1 mediates SPARC-dependent collagen deposition in the aging myocardium.
abstract: Secreted protein acidic and rich in cysteine (SPARC) is a collagen-binding matricellular protein highly expressed during fibrosis. Fibrosis is a prominent component of cardiac aging that reduces myocardial elasticity. Previously, we reported that SPARC deletion attenuated myocardial stiffness and collagen deposition in aged mice. To investigate the mechanisms by which SPARC promotes age-related cardiac fibrosis, we evaluated six groups of mice (n = 5-6/group): young (3-5 mo old), middle-aged (10-12 mo old), and old (18-29 mo old) C57BL/6 wild type (WT) and SPARC-null (Null) mice. Collagen content, determined by picrosirius red staining, increased in an age-dependent manner in WT but not in Null mice. A disintegrin and metalloproteinase with thrombospondin-like motifs 1 (ADAMTS1) increased in middle-aged and old WT compared with young, whereas in Null mice only old animals showed increased ADAMTS1 expression. Versican, a substrate of ADAMTS1, decreased with age only in WT. To assess the mechanisms of SPARC-induced collagen deposition, we stimulated cardiac fibroblasts with SPARC. SPARC treatment increased secretion of collagen I and ADAMTS1 (both the 110-kDa latent and 87-kDa active forms) into the conditioned media as well as the cellular expression of transforming growth factor-β1-induced protein (Tgfbi) and phosphorylated Smad2. An ADAMTS1 blocking antibody suppressed the SPARC-induced collagen I secretion, indicating that SPARC promoted collagen production directly through ADAMTS1 interaction. In conclusion, ADAMTS1 is an important mediator of SPARC-regulated cardiac aging.
authors.affiliation: Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan; toba@mb.kyoto-phu.ac.jp.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Toba
authors.affiliation: Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; Department of Physiology, East Carolina University, Greenville, North Carolina;
authors.forename: Lisandra E
authors.initials: LE
authors.lastname: de Castro Brás
authors.affiliation: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Catalin F
authors.initials: CF
authors.lastname: Baicu
authors.affiliation: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi; G. V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, Mississippi.
authors.forename: Merry L
authors.identifier: 0000-0002-4090-0391
authors.initials: ML
authors.lastname: Lindsey
authors.affiliation: Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Bradshaw
mesh_terms: D000071097:ADAMTS1 Protein / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D015676:Osteonectin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; D015676:Osteonectin; C578250:SPARC protein, mouse; D003094:Collagen; D000071097:ADAMTS1 Protein; C486323:Adamts1 protein, mouse
keywords: a disintegrin and metalloproteinase with thrombospondin-like motifs 1; fibroblast; heart; matrix metalloproteinase; secreted protein acidic and rich in cysteine