SCMH staff paper published in Cardiovascular Research

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

*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

Link to paper: academic.oup.com

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.

* The first two authors Weihong He and Charlotte S McCarroll are joint first authors.


First published: 1 September 2021