Dataset Information

The role of cathepsin D in the pathophysiology of heart failure and its potentially beneficial properties: a translational approach.

ABSTRACT:

Aims

Cathepsin D is a ubiquitous lysosomal protease that is primarily secreted due to oxidative stress. The role of circulating cathepsin D in heart failure (HF) is unknown. The aim of this study is to determine the association between circulating cathepsin D levels and clinical outcomes in patients with HF and to investigate the biological settings that induce the release of cathepsin D in HF.

Methods and results

Cathepsin D levels were studied in 2174 patients with HF from the BIOSTAT-CHF index study. Results were validated in 1700 HF patients from the BIOSTAT-CHF validation cohort. The primary combined outcome was all-cause mortality and/or HF hospitalizations. Human pluripotent stem cell-derived cardiomyocytes were subjected to hypoxic, pro-inflammatory signalling and stretch conditions. Additionally, cathepsin D expression was inhibited by targeted short hairpin RNAs (shRNA). Higher levels of cathepsin D were independently associated with diabetes mellitus, renal failure and higher levels of interleukin-6 and N-terminal pro-B-type natriuretic peptide (P < 0.001 for all). Cathepsin D levels were independently associated with the primary combined outcome [hazard ratio (HR) per standard deviation (SD): 1.12; 95% confidence interval (CI) 1.02-1.23], which was validated in an independent cohort (HR per SD: 1.23, 95% CI 1.09-1.40). In vitro experiments demonstrated that human stem cell-derived cardiomyocytes released cathepsin D and troponin T in response to mechanical stretch. ShRNA-mediated silencing of cathepsin D resulted in increased necrosis, abrogated autophagy, increased stress-induced metabolism, and increased release of troponin T from human stem cell-derived cardiomyocytes under stress.

Conclusions

Circulating cathepsin D levels are associated with HF severity and poorer outcome, and reduced levels of cathepsin D may have detrimental effects with therapeutic potential in HF.

SUBMITTER: Hoes MF

PROVIDER: S-EPMC7754332 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The role of cathepsin D in the pathophysiology of heart failure and its potentially beneficial properties: a translational approach.

Hoes Martijn F MF Tromp Jasper J Ouwerkerk Wouter W Bomer Nils N Oberdorf-Maass Silke U SU Samani Nilesh J NJ Ng Leong L LL Lang Chim C CC van der Harst Pim P Hillege Hans H Anker Stefan D SD Metra Marco M van Veldhuisen Dirk J DJ Voors Adriaan A AA van der Meer Peter P

European journal of heart failure 20191203 11

<h4>Aims</h4>Cathepsin D is a ubiquitous lysosomal protease that is primarily secreted due to oxidative stress. The role of circulating cathepsin D in heart failure (HF) is unknown. The aim of this study is to determine the association between circulating cathepsin D levels and clinical outcomes in patients with HF and to investigate the biological settings that induce the release of cathepsin D in HF.<h4>Methods and results</h4>Cathepsin D levels were studied in 2174 patients with HF from the B ...[more]

PMID: 31797504

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Dataset Information

The role of cathepsin D in the pathophysiology of heart failure and its potentially beneficial properties: a translational approach.

Aims

Methods and results

Conclusions

Publications

The role of cathepsin D in the pathophysiology of heart failure and its potentially beneficial properties: a translational approach.

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