Increased ADAMTS1 mediates SPARC-dependent collagen deposition in the aging myocardium.
Hiroe TobaLisandra E de Castro BrásCatalin F BaicuMichael R ZileMerry L LindseyAmy D BradshawPublished in: American journal of physiology. Endocrinology and metabolism (2016)
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.
Keyphrases
- wild type
- left ventricular
- transforming growth factor
- wound healing
- high fat diet induced
- middle aged
- tissue engineering
- poor prognosis
- high glucose
- binding protein
- diabetic rats
- epithelial mesenchymal transition
- amino acid
- heart failure
- transcription factor
- protein protein
- drug induced
- heat shock protein
- adipose tissue
- skeletal muscle
- small molecule
- dna binding
- atrial fibrillation
- smoking cessation
- combination therapy