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 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.

• Authors: Weihong He, Charlotte S McCarroll, Katrin Nather, Kristopher Ford, Kenneth Mangion, Alexandra Riddell, Dylan O'Toole, Ali Zaeri, David Corcoran, David Carrick, Mathew M Y Lee, Margaret McEntegart, Andrew Davie, Richard Good, Mitchell M Lindsay, Hany Eteiba, Paul Rocchiccioli, Stuart Watkins, Stuart Hood, Aadil Shaukat, Lisa McArthur, Elspeth B Elliott, John McClure, Catherine Hawksby, Tamara Martin, Mark C Petrie, Keith G Oldroyd, Godfrey L Smith, Oxford Acute Myocardial Infarction (OxAMI) Study, Keith M Channon, Colin Berry, Stuart A Nicklin, Christopher M Loughrey
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 118 Issue 6 Pg. 1535-1547 (05 06 2022) ISSN: 1755-3245 [Electronic] England
• PMID: 34132807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Chemical References

• Cathepsins

Topics

• Cathepsins
• Humans
• Myocardial Infarction (therapy)
• Myocardial Reperfusion (adverse effects)
• Myocardial Reperfusion Injury (prevention & control)
• Percutaneous Coronary Intervention (adverse effects)
• Reperfusion
• ST Elevation Myocardial Infarction
• Treatment Outcome