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Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice.

ABSTRACT: 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 μmol/mg tissue/min; CatA-TG, 8.62 μmol/mg tissue/min), increased inflammation, myocyte hypertrophy (WT, 19.8 μm; CatA-TG, 21.9 μm), 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 μl; CatA-TG, 61.9 μl). 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.

SUBMITTER: Hohl M

PROVIDER: S-EPMC7476717 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice.

Hohl Mathias M Mayr Manuel M Lang Lisa L Nickel Alexander G AG Barallobre-Barreiro Javier J Yin Xiaoke X Speer Thimoteus T Selejan Simina-Ramona SR Goettsch Claudia C Erb Katharina K Fecher-Trost Claudia C Reil Jan-Christian JC Linz Benedikt B Ruf Sven S Hübschle Thomas T Maack Christoph C Böhm Michael M Sadowski Thorsten T Linz Dominik D

The Journal of biological chemistry 20200709 36

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 ( ...[more]

PMID: 32647007

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Project description:Extracellular superoxide dismutase (ecSOD) protects the extracellular matrix from oxidative stress. We previously reported a new allele for ecSOD, expressed in 129P3/J mice (129), which differs from the wild type (wt), expressed in C57BL/6J and other strains, by two amino acid substitutions and a 10-bp deletion in the 3' UTR of the mRNA (A. Pierce et al., 2003, Arterioscler. Thromb. Vasc. Biol.23:1820-1825). The newly discovered allele is associated with a phenotype of significantly increased circulating and heparin-releasable enzyme activities and levels. To examine the properties of the two forms of ecSOD in an identical environment we generated, by extensive backcrossing of ecSOD heterozygous progeny to C57BL/6J females, a congenic C57 strain with the 129 (or wt) allele of ecSOD. These mice are homozygous for nearly 5000 SNPs across all chromosomes, as determined by the Affymetrix Parallele Mouse 5K SNP panel. This study describes the generation of the congenic mice (genetically >99.8% identical) and their ecSOD phenotype. The congenic mouse plasma ecSOD activity before and after heparin administration recapitulates the differences reported in the founder mice. Tissue enzyme distribution is similar in both congenic groups, although the 129 allele is associated with higher levels of enzyme expression despite lower levels of enzyme mRNA. In these characteristics the phenotype is allele driven, with little impact from the rest of the genome. The congenic mice carrying the 129 allele have mRNA levels that are in between those in the founder 129P3/J and C57BL/6J strains. We conclude that the ecSOD phenotype in most aspects of enzyme expression is allele driven, with the exception of tissue mRNA levels, for which a significant contribution by the surrounding (host) genome is observed. These results also suggest potential allele-specific differences in the regulation of ecSOD synthesis and intracellular processing/secretion of ecSOD, independent of the genotype context. Most importantly, the congenic mice offer an excellent model to examine the regulatory mechanisms of ecSOD expression and the role of ecSOD in various diseases involving oxidative stress.

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Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice.

Publications

Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice.

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