Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice
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- Cathepsin A contributes to left ventricular remodeling by
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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 mu mol/mg tissue/min; CatA-TG, 8.62 mu mol/mg tissue/min), increased inflammation, myocyte hypertrophy (WT, 19.8 mu m; CatA-TG, 21.9 mu m), 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 mu l; CatA-TG, 61.9 mu l). 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.
Original language | English |
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Journal | Journal of Biological Chemistry |
Volume | 295 |
Issue number | 36 |
Pages (from-to) | 12605-12617 |
ISSN | 0021-9258 |
DOIs | |
Publication status | Published - 2020 |
- cathepsin A, carboxypeptidase, extracellular matrix protein, oxidative stress, extracellular superoxide dismutase, cardiac hypertrophy, cardiac remodeling, left ventricular dysfunction, heart disease, secretome, superoxide dismutase (SOD), oxygen radicals, heart failure, fibrosis, EC-SOD, OXIDATIVE STRESS, HEART, HYPERTROPHY, PROTECTS, COLLAGEN, MATRIX, REPAIR
Research areas
ID: 251791143