Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice
Mathias Hohl, Manuel Mayr, Lisa A. Lang, Alexander 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 Hübschle, Christoph Maack, Michael Böhm, Thorsten Sadowski, Dominik Linz
Abstract
, 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.