Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice. / Hohl, Mathias; Mayr, Manuel; Lang, Lisa; Nickel, Alexander G.; Barallobre-Barreiro, Javier; Yin, Xiaoke; Speer, Thimoteus; Selejan, Simina-Ramona; Goettsch, Claudia; Erb, Katharina; Fecher-Trost, Claudia; Reil, Jan-Christian; Linz, Benedikt; Ruf, Sven; Huebschle, Thomas; Maack, Christoph; Boehm, Michael; Sadowski, Thorsten; Linz, Dominik.
In: Journal of Biological Chemistry, Vol. 295, No. 36, 2020, p. 12605-12617.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice
AU - Hohl, Mathias
AU - Mayr, Manuel
AU - Lang, Lisa
AU - Nickel, Alexander G.
AU - Barallobre-Barreiro, Javier
AU - Yin, Xiaoke
AU - Speer, Thimoteus
AU - Selejan, Simina-Ramona
AU - Goettsch, Claudia
AU - Erb, Katharina
AU - Fecher-Trost, Claudia
AU - Reil, Jan-Christian
AU - Linz, Benedikt
AU - Ruf, Sven
AU - Huebschle, Thomas
AU - Maack, Christoph
AU - Boehm, Michael
AU - Sadowski, Thorsten
AU - Linz, Dominik
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - cathepsin A
KW - carboxypeptidase
KW - extracellular matrix protein
KW - oxidative stress
KW - extracellular superoxide dismutase
KW - cardiac hypertrophy
KW - cardiac remodeling
KW - left ventricular dysfunction
KW - heart disease
KW - secretome
KW - superoxide dismutase (SOD)
KW - oxygen radicals
KW - heart failure
KW - fibrosis
KW - EC-SOD
KW - OXIDATIVE STRESS
KW - HEART
KW - HYPERTROPHY
KW - PROTECTS
KW - COLLAGEN
KW - MATRIX
KW - REPAIR
U2 - 10.1074/jbc.RA120.013488
DO - 10.1074/jbc.RA120.013488
M3 - Journal article
C2 - 32647007
VL - 295
SP - 12605
EP - 12617
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 36
ER -
ID: 251791143