The Cathepsin-L Inhibitor CAA0225 Improves Cardiac Function During Ischaemia-Reperfusion

Abstract

Cathepsins are lysosomal cysteine proteases involved in molecular signaling and protein degradation. Importantly, these proteases can also be secreted into the extracellular space. Cathepsin-L is elevated in the serum of patients with ischaemic heart disease and correlates with disease severity. Our data demonstrate that cathepsin-L levels are increased in the coronary effluent of ex vivo rat hearts after a period of 30 min ischaemia, however the contribution of cathepsin-L to cardiac contractile function remains unknown. Using a cathepsin-L inhibitor (CAA0225), we investigated the hypothesis that cathepsin-L contributes to contractile dysfunction post ischaemia. Langendorff perfused ex vivo adult rat hearts under went 30 min whole heart ischaemia followed by 90 min reperfusion. Left ventricular (LV) function was assessed using a solid-state pressure catheter within a balloon in the LV cavity. In separate cohorts of hearts, CAA0225 or DMSO (control) was applied for 25 min prior to ischaemia. CAA0225 had no effect on LV developed pressure prior to ischaemia. However, during reperfusion post-ischaemia CAA0225 led to a sustained increase of LV developed pressure to 177% of control levels at 90 min reperfusion (25.1 vs. 44.5 % developed LV pressure of pre-ischaemia level; DSMO [n=15] vs. CAA0225 [n=6]; P<0.05). The maximum rate of rise and fall in developed LV pressure were also elevated by CAA0225 by 169% and 151% respectively. Whilst there was no significant difference in the minimum LV pressure during the ischaemic period, this parameter was reduced during reperfusion which after 90 min was 68% of control levels (78.0 vs. 53.0 mmHg; DSMO [n=15] vs. CAA0225 [n=6]; P<0.05). These data demonstrate for the first time that the cathepsin-L inhibitor CAA0225 improves both systolic and diastolic cardiac functional parameters during ischaemia-reperfusion in ex vivo adult rat hearts.