Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice
| Autor: | Michael Böhm, Jan-Christian Reil, Manuel Mayr, Christoph Maack, Thomas Hübschle, Thorsten Sadowski, Alexander Nickel, Claudia Goettsch, Benedikt Linz, Sven Ruf, Thimoteus Speer, Dominik Linz, Simina-Ramona Selejan, Javier Barallobre-Barreiro, Xiaoke Yin, Claudia Fecher-Trost, Lisa Lang, Katharina Erb, Mathias Hohl |
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| Přispěvatelé: | Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H08 Experimental atrial fibrillation |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine cathepsin A heart failure heart disease medicine.disease_cause Biochemistry Cathepsin A Extracellular matrix PROTECTS Mice Fibrosis oxygen radicals oxidative stress Myocytes Cardiac EC-SOD left ventricular dysfunction Ventricular Remodeling biology Chemistry cardiac hypertrophy Molecular Bases of Disease extracellular matrix protein carboxypeptidase HEART Intracellular extracellular superoxide dismutase superoxide dismutase (SOD) Mice Transgenic Superoxide dismutase 03 medical and health sciences medicine Extracellular Animals Ventricular remodeling Molecular Biology REPAIR 030102 biochemistry & molecular biology Superoxide Dismutase fibrosis Cell Biology medicine.disease Molecular biology COLLAGEN HYPERTROPHY secretome 030104 developmental biology Proteolysis biology.protein cardiac remodeling MATRIX Oxidative stress |
| Zdroj: | Journal of Biological Chemistry, 295(36), 12605-12617. American Society for Biochemistry and Molecular Biology, Inc. Hohl, M, Mayr, M, Lang, L, Nickel, A G, Barallobre-Barreiro, J, Yin, X, Speer, T, Selejan, S-R, Goettsch, C, Erb, K, Fecher-Trost, C, Reil, J-C, Linz, B, Ruf, S, Huebschle, T, Maack, C, Boehm, M, Sadowski, T & Linz, D 2020, ' Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice ', Journal of Biological Chemistry, vol. 295, no. 36, pp. 12605-12617 . https://doi.org/10.1074/jbc.RA120.013488 J Biol Chem |
| ISSN: | 1083-351X 0021-9258 |
| DOI: | 10.1074/jbc.RA120.013488 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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