Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size. Issue 6 (16th June 2021)

• Record Type: Journal Article
• 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;
• Is Part Of: Cardiovascular research. Volume 118:Issue 6(2022)
• Page Start: 1535
• Page End: 1547
• Publication Date: 2021-06-16
• Subjects: Myocardial infarction -- Reperfusion injury -- Cardiomyocytes -- Calcium -- Sarcoplasmic reticulum; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvab204
• Languages: English
• ISSNs: 0008-6363

Abstract

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.