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. We previously 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 6 groups of mice (n=5-6/group): young (3-5 month old), middle-aged (10-12 month old) and old (18-29 month 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 type 1 motif, 1 (ADAMTS1) increased in middle-aged and old WT compared to 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 110kDa latent and 87 kDa active forms) into the conditioned media, as well as increased 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.
- secreted protein acidic and rich in cysteine
- matrix metalloproteinase
- a disintegrin and metalloproteinase with thrombospondin type 1 motif, 1
- Copyright © 2016, American Journal of Physiology - Endocrinology and Metabolism