Attenuation of increased myocardial ischaemia‐reperfusion injury conferred by hypercholesterolaemia through pharmacological inhibition of the caspase‐1 cascade

Hypercholesterolaemia has been shown to be associated with greater myocardial ischaemia‐reperfusion injury, in which apoptosis and inflammation‐mediated necrosis both play a key role. Caspase‐1 is involved in the activation of both apoptosis and inflammation, through the intermediate of interleukin‐1β (IL‐1β). We herein examined whether pharmacological inhibition of the caspase‐1 cascade, using Ac‐Tyr‐Val‐Ala‐Asp‐CH 2 Cl (Ac‐YVAD.cmk), after myocardial ischaemia have greater protective effects on myocardial ischaemia‐reperfusion injury in diet‐induced hypercholesterolaemic rabbits. Male rabbits fed with standard chow or chow supplemented with 0.5% cholesterol and 10% coconut oil for 8 weeks were subjected to 30 min of left circumflex artery occlusion followed by 4 h of reperfusion. An intravenous bolus of Ac‐YVAD.cmk (1.6 mg kg −1 ) or vehicle was given 20 min after coronary occlusion. Postischaemic administration of Ac‐YVAD.cmk markedly decreased infarct size from 26±3% to 12±2% in normally fed rabbits ( P =0.005) and from 41±6% to 14±2% in cholesterol‐fed rabbits ( P <0.001). In the ischaemic non‐necrotic area, treatment with Ac‐YVAD.cmk markedly reduced the percentage of terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labelling (TUNEL)‐positive cardiomyocytes from 15.5±0.8% to 2.2±0.1% in normally fed rabbits ( P <0.001) and from 39.0±2.3% to 2.2±0.1% in cholesterol‐fed rabbits ( P <0.001). Ac‐YVAD.cmk treatment resulted in a reduction not only of IL‐1β and caspase‐1, but also of caspase‐3 in the ischaemic myocardium in both normally fed and cholesterol‐fed rabbits. No differences in infarct size, the percentage of TUNEL‐positive cardiomyocytes, IL‐1β levels or activity of caspase‐1 and caspase‐3 were observed between Ac‐YVAD.cmk‐treated normally fed and cholesterol‐fed rabbits. This study demonstrates that injection of a selective caspase‐1 inhibitor after myocardial ischaemia markedly reduced the detrimental effect conferred by hypercholesterolaemia on myocardial ischaemia‐reperfusion injury by attenuating both necrotic as well as apoptotic cell death pathways through inhibition of IL‐1β production and activation of caspase‐1 and caspase‐3.British Journal of Pharmacology (2003) 138 , 291–300. doi: 10.1038/sj.bjp.0705098