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

Mathias Hohl, Manuel Mayr, Lisa Lang, Alexander G. Nickel, Javier Barallobre-Barreiro, Xiaoke Yin, Thimoteus Speer, Simina-Ramona Selejan, Claudia Goettsch, Katharina Erb, Claudia Fecher-Trost, Jan-Christian Reil, Benedikt Linz, Sven Ruf, Thomas Huebschle, Christoph Maack, Michael Boehm, Thorsten Sadowski, Dominik Linz*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

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 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 languageEnglish
Pages (from-to)12605-12617
Number of pages13
JournalJournal of Biological Chemistry
Volume295
Issue number36
DOIs
Publication statusPublished - 4 Sep 2020

Keywords

  • 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

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