Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size

He, W. et al. (2022) Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size. Cardiovascular Research, 118(6), pp. 1535-1547. (doi: 10.1093/cvr/cvab204) (PMID:34132807)

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Aims: Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevated myocardial infarction (STEMI) to heart failure. Here we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. Methods and Results: We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 hour post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies, demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. Conclusion: Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI. Translational perspective: New therapeutic targets are urgently required to limit myocardial damage after reperfusion injury. We identified cardiac release of the protease cathepsin-L among patients following primary percutaneous coronary intervention (PPCI). Elevated serum levels of cathepsin-L were associated with reduced contractile function and increased infarct size at 24 hour and 6 months post-PPCI. Work conducted using animal models indicated that cardiac release of cathepsin-L mediated cardiac dysfunction following reperfusion injury. Specific inhibition of cathepsin-L prevented abnormal calcium handling, reduced infarct size and improved contractile function. These novel findings offer the prospect of targeting cathepsin-L-mediated cardiac dysfunction after PPCI.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Zaeri, Ali Abdullah I and Corcoran, Dr David and Hood, Dr Stuart and O'Toole, Mr Dylan and Eteiba, Professor Hany and McArthur, Dr Lisa and Martin, Dr Tamara and Lee, Matthew and Nicklin, Professor Stuart and Petrie, Professor Mark and He, Weihong and McClure, Dr John and Smith, Professor Godfrey and McEntegart, Dr Margaret and Carrick, Dr David and Mangion, Dr Kenneth and Loughrey, Professor Christopher and Shaukat, Dr Aadil and Hawksby, Mrs Catherine and Nather, Katrin and Oldroyd, Dr Keith and Watkins, Dr Stuart and Berry, Professor Colin and Riddell, Dr Alexandra and McCarroll, Dr Charlotte and Elliott, Dr Elspeth
Authors: He, W., McCarroll, C. S., Nather, K., Ford, K., Mangion, K., Riddell, A., O'Toole, D., Zaeri, A., Corcoran, D., Carrick, D., Lee, M. M.Y., McEntegart, M., Davie, A., Good, R., Lindsay, M. M., Eteiba, H., Rocchiccioli, P., Watkins, S., Hood, S., Shaukat, A., McArthur, L., Elliott, E. B., McClure, J., Hawksby, C., Martin, T., Petrie, M. C., Oldroyd, K. G., Smith, G. L., Channon, K. M., Berry, C., Nicklin, S. A., and Loughrey, C. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Cardiovascular Research
Publisher:Oxford University Press
ISSN (Online):1755-3245
Published Online:16 June 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Cardiovascular Research 118(6): 1535-1547
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
167523Investigating the therapeutic potential of cathepsin-L inhibition to limit ischaemia-reperfusion injury in the heartChristopher LoughreyOffice of the Chief Scientific Adviser (CSO)ETM/263Institute of Cardiovascular & Medical Sciences
190536Integrated Health - Polyomics and Systems Biomedicine (ISSF Bid)Anna DominiczakWellcome Trust (WELLCOTR)097821/Z/11/ZInstitute of Cardiovascular & Medical Sciences
172173Myocardial strain measurements in survivors of acute ST-elevation myocardial infarction: implementation and prognostic significance of novel magnetic resonance imaging methods.Colin BerryBritish Heart Foundation (BHF)FS/15/54/31639Institute of Cardiovascular & Medical Sciences
166711Serum phosphate as a cardiovascular risk factor: effects on vascular and endothelial functionKathryn StevensBritish Heart Foundation (BHF)FS/12/28/29417Institute of Cardiovascular & Medical Sciences
308798Targeting RUNX to Attenuate Adverse Cardiac RemodellingChristopher LoughreyBritish Heart Foundation (BHF)RG/20/6/35095Vets - Veterinary Pathology, Public Health & Disease Investigation