The Role of Cathepsin D in the Pathophysiology of Heart Failure and its Potentially Beneficial Properties: a translational approach

TY - JOUR

T1 - The Role of Cathepsin D in the Pathophysiology of Heart Failure and its Potentially Beneficial Properties

T2 - a translational approach

AU - Hoes, Martijn F.

AU - Tromp, Jasper

AU - Ouwerkerk, Wouter

AU - Bomer, Nils

AU - Oberdorf-Maas, Silke U.

AU - Samani, Nilesh J.

AU - Ng, Leong Loke

AU - Lang, Chim

AU - van der Harst, Pim

AU - Hillege, Hans L.

AU - Anker, Stefan D.

AU - Metra, Marco

AU - van Veldhuisen, Dirk J.

AU - Voors, Adriaan A.

AU - van der Meer, Peter

N1 - Funding Information European Commission. Grant Numbers: FP7‐242209‐BIOSTAT‐CHF, EudraCT 2010–020808–29

PY - 2020/11

Y1 - 2020/11

N2 - 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.

AB - 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.

KW - BIOSTAT-CHF

KW - Biomarkers

KW - Cathepsin D

KW - Heart failure

KW - Human stem cell-derived cardiomyocytes

UR - https://www.scopus.com/pages/publications/85076180922

U2 - 10.1002/ejhf.1674

DO - 10.1002/ejhf.1674

M3 - Article

C2 - 31797504

SN - 1388-9842

VL - 22

SP - 2102

EP - 2111

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

IS - 11

ER -