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-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. 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 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. 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. Translational perspective 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.

Pharmacological inhibition of RUNX1 reduces infarct size after acute myocardial infarction in rats and underlying mechanism revealed by proteomics implicates repressed cathepsin levels

“…Here, we utilized a small molecule inhibitor (Ro5-3335) as a means of antagonizing RUNX1 and examined its effects on infarct size in the context of acute MI. Adult male Wistar rats were subjected to thoracotomy and left anterior descending coronary artery ligation through approaches we previously established (McCarroll et al 2018 ; He et al 2022 ). Ro5-3335 was administered immediately following coronary artery ligation by intraperitoneal injection at a dose of 10 mg/kg based on the previous study defining its effects on cardiac contractile function post-MI (Martin et al 2023 ).…”

“…Our previous study has shown that programmed cell death pathways can be therapeutically targeted to limit infarct size. He et al (He et al 2022 ) demonstrated activated apoptosis in cardiomyocytes obtained from ex vivo isolated rat hearts which are subjected to ischemia followed by reperfusion. Pharmacological treatment antagonizing cathepsin-L in ex vivo hearts showed effects of suppressing apoptosis and reducing infarct size (He et al 2022 ).…”

Early plasma proteomic biomarkers and prediction model of acute respiratory distress syndrome after cardiopulmonary bypass: a prospective nested cohort study

“…The circulating and tissue levels of CTSL were elevated after SARS-CoV-2 infection 36 , suggesting that CTSL is likely to be a potential therapeutic target for blocking viral entry 36 , 37 . CTSL has been linked to IR injury, including renal IR injury 38 and myocardial IR injury 39 . Consistent with previous studies, we also reported the crucial role of CTSL in the plasma of CPB-ARDS patients and the lung tissue of LIRI rats.…”

Inhibiting Runx1 protects heart function after myocardial infarction

“…Thoracotomy and left anterior descending coronary artery permanent ligation surgeries were performed on C57BL/6J (Envigo), Runx1- deficient, Cbfβ- deficient and respective floxed control mice using previously published standard approaches (see Extended Methods) 59, 60 .…”