ADAMTS1
A disintegrin and metalloproteinase with thrombospondin motifs 1 precursor (EC 3.4.24.-) (ADAM-TS 1) (ADAM-TS1) (ADAMTS-1) (METH-1) [KIAA1346] [METH1]
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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.
MeSH Terms
- ADAMTS1 Protein
- Aging
- Animals
- Cells, Cultured
- Collagen
- Extracellular Matrix
- Extracellular Matrix Proteins
- Female
- Fibroblasts
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myocardium
- Osteonectin
- Signal Transduction
- Up-Regulation
Keywords
- a disintegrin and metalloproteinase with thrombospondin-like motifs 1
- fibroblast
- heart
- matrix metalloproteinase
- secreted protein acidic and rich in cysteine
The metalloprotease ADAMTS9 participates in melanoblast development and is a tumor suppressor in esophageal and nasopharyngeal cancer. ADAMTS9 null mice die before gastrulation, but, ADAMTS9 /- mice were initially thought to be normal. However, when congenic with the C57Bl/6 strain, 80% of ADAMTS9 /- mice developed spontaneous corneal neovascularization. beta-Galactosidase staining enabled by a lacZ cassette targeted to the ADAMTS9 locus showed that capillary endothelial cells (ECs) in embryonic and adult tissues and in capillaries growing into heterotopic tumors expressed ADAMTS9. Heterotopic B.16-F10 melanomas elicited greater vascular induction in ADAMTS9 /- mice than in wild-type littermates, suggesting a potential inhibitory role in tumor angiogenesis. Treatment of cultured human microvascular ECs with ADAMTS9 small-interfering RNA resulted in enhanced filopodial extension, decreased cell adhesion, increased cell migration, and enhanced formation of tube-like structures on Matrigel. Conversely, overexpression of catalytically active, but not inactive, ADAMTS9 in ECs led to fewer tube-like structures, demonstrating that the proteolytic activity of ADAMTS9 was essential. However, unlike the related metalloprotease ADAMTS1, which exerts anti-angiogenic effects by cleavage of thrombospondins and sequestration of vascular endothelial growth factor165, ADAMTS9 neither cleaved thrombospondins 1 and 2, nor bound vascular endothelial growth factor165. Taken together, these data identify ADAMTS9 as a novel, constitutive, endogenous angiogenesis inhibitor that operates cell-autonomously in ECs via molecular mechanisms that are distinct from those used by ADAMTS1.
MeSH Terms
- ADAM Proteins
- ADAMTS9 Protein
- Aging
- Animals
- Biocatalysis
- Cell Movement
- Corneal Neovascularization
- Embryo, Mammalian
- Endothelial Cells
- Enzyme Activation
- Gene Knockdown Techniques
- Humans
- Mice
- Mice, Inbred C57BL
- Microvessels
- Neoplasm Transplantation
- Neoplasms
- Neovascularization, Pathologic
- Organ Specificity
- Phosphorylation
- RNA, Messenger
- RNA, Small Interfering
- Receptors, Vascular Endothelial Growth Factor
- Thrombospondin 1
- Thrombospondins
- Vascular Endothelial Growth Factor A