| First Author | Hohl M | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 36 | Pages | 12605-12617 |
| PubMed ID | 32647007 | Mgi Jnum | J:298728 |
| Mgi Id | MGI:6477854 | Doi | 10.1074/jbc.RA120.013488 |
| Citation | Hohl M, et al. (2020) Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice. J Biol Chem 295(36):12605-12617 |
| abstractText | In the heart, the serine carboxypeptidase cathepsin A (CatA) is distributed between lysosomes and the extracellular matrix (ECM). CatA-mediated degradation of extracellular peptides may contribute to ECM remodeling and left ventricular (LV) dysfunction. Here, we aimed to evaluate the effects of CatA overexpression on LV remodeling. A proteomic analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA, which decreased EC-SOD abundance 5-fold. In vitro, both cardiomyocytes and cardiac fibroblasts expressed and secreted CatA protein, and only cardiac fibroblasts expressed and secreted EC-SOD protein. Cardiomyocyte-specific CatA overexpression and increased CatA activity in the LV of transgenic mice (CatA-TG) reduced EC-SOD protein levels by 43%. Loss of EC-SOD-mediated antioxidative activity resulted in significant accumulation of superoxide radicals (WT, 4.54 mumol/mg tissue/min; CatA-TG, 8.62 mumol/mg tissue/min), increased inflammation, myocyte hypertrophy (WT, 19.8 mum; CatA-TG, 21.9 mum), cellular apoptosis, and elevated mRNA expression of hypertrophy-related and profibrotic marker genes, without affecting intracellular detoxifying proteins. In CatA-TG mice, LV interstitial fibrosis formation was enhanced by 19%, and the type I/type III collagen ratio was shifted toward higher abundance of collagen I fibers. Cardiac remodeling in CatA-TG was accompanied by an increased LV weight/body weight ratio and LV end diastolic volume (WT, 50.8 mul; CatA-TG, 61.9 mul). In conclusion, CatA-mediated EC-SOD reduction in the heart contributes to increased oxidative stress, myocyte hypertrophy, ECM remodeling, and inflammation, implicating CatA as a potential therapeutic target to prevent ventricular remodeling. |
