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

Abstract 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-elevation myocardial infarction (STEMI) to heart failure. Here, we show through paral...

Full description

Saved in:
Bibliographic Details
Published in:Cardiovascular research 2022-05, Vol.118 (6), p.1535-1547
Main Authors: He, Weihong, McCarroll, Charlotte S, Nather, Katrin, Ford, Kristopher, Mangion, Kenneth, Riddell, Alexandra, O’Toole, Dylan, Zaeri, Ali, Corcoran, David, Carrick, David, Lee, Mathew M Y, McEntegart, Margaret, Davie, Andrew, Good, Richard, Lindsay, Mitchell M, Eteiba, Hany, Rocchiccioli, Paul, Watkins, Stuart, Hood, Stuart, Shaukat, Aadil, McArthur, Lisa, Elliott, Elspeth B, McClure, John, Hawksby, Catherine, Martin, Tamara, Petrie, Mark C, Oldroyd, Keith G, Smith, Godfrey L, Channon, Keith M, Berry, Colin, Nicklin, Stuart A, Loughrey, Christopher M
Format: Article
Language:English
Subjects:
Cathepsins
Humans
Myocardial Infarction - therapy
Myocardial Reperfusion - adverse effects
Myocardial Reperfusion Injury - prevention & control
Original
Percutaneous Coronary Intervention - adverse effects
Reperfusion
ST Elevation Myocardial Infarction
Treatment Outcome
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract 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-elevation 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 h 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.
ISSN:0008-6363
1755-3245
1755-3245
DOI:10.1093/cvr/cvab204