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.

• Authors: Martijn F Hoes, Jasper Tromp, Wouter Ouwerkerk, Nils Bomer, Silke U Oberdorf-Maass, Nilesh J Samani, Leong L Ng, Chim C Lang, Pim van der Harst, Hans Hillege, Stefan D Anker, Marco Metra, Dirk J van Veldhuisen, Adriaan A Voors, Peter van der Meer
• Journal: European journal of heart failure (Eur J Heart Fail) Vol. 22 Issue 11 Pg. 2102-2111 (11 2020) ISSN: 1879-0844 [Electronic] England
• PMID: 31797504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Chemical References

• Angiotensin Receptor Antagonists
• Angiotensin-Converting Enzyme Inhibitors
• Biomarkers
• Peptide Fragments
• pro-brain natriuretic peptide (1-76)
• Natriuretic Peptide, Brain
• CTSD protein, human
• Cathepsin D

Topics

• Aged
• Angiotensin Receptor Antagonists (therapeutic use)
• Angiotensin-Converting Enzyme Inhibitors
• Biomarkers (blood)
• Cathepsin D (blood)
• Female
• Heart Failure (blood, enzymology, physiopathology, therapy)
• Humans
• Male
• Natriuretic Peptide, Brain (blood)
• Peptide Fragments (blood)
• Percutaneous Coronary Intervention
• Prognosis
• Ventricular Function, Left