Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size
| Autor: | Elspeth B. Elliott, Aadil Shaukat, Weihong He, Kristopher Ford, Lisa McArthur, Katrin Nather, Mitchell Lindsay, Colin Berry, Stuart Hood, Ali Abdullah I. Zaeri, Catherine Hawksby, Tamara P. Martin, John D. McClure, Keith G. Oldroyd, David Carrick, Paul Rocchiccioli, Hany Eteiba, Keith M. Channon, Andrew Davie, Dylan O'Toole, Margaret McEntegart, Mark C. Petrie, Kenneth Mangion, Charlotte S. McCarroll, Stuart Watkins, Mathew M Y Lee, Stuart A. Nicklin, David Corcoran, Christopher M. Loughrey, Richard Good, Alexandra Riddell, Godfrey L. Smith |
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| Přispěvatelé: | Study, Oxford Acute Myocardial Infarction (OxAMI) |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cardiac function curve medicine.medical_specialty Physiology medicine.medical_treatment Myocardial Infarction chemistry.chemical_element Myocardial Reperfusion Myocardial Reperfusion Injury 030204 cardiovascular system & hematology Calcium Cathepsin L 03 medical and health sciences Percutaneous Coronary Intervention 0302 clinical medicine Physiology (medical) Internal medicine medicine Humans Myocardial infarction biology business.industry Percutaneous coronary intervention medicine.disease Cathepsins Treatment Outcome 030104 developmental biology chemistry Apoptosis Heart failure Reperfusion Cardiology biology.protein ST Elevation Myocardial Infarction Cardiology and Cardiovascular Medicine business Reperfusion injury |
| Zdroj: | Cardiovascular Research. 118:1535-1547 |
| ISSN: | 1755-3245 0008-6363 |
| DOI: | 10.1093/cvr/cvab204 |
| Popis: | Aims: \ud 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.\ud \ud Methods and Results: \ud 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.\ud \ud Conclusion: \ud 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.\ud \ud Translational perspective: \ud 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. |
| Databáze: | OpenAIRE |
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