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36 Cyclophilin-D ablation offers long-term protection against acute myocardial ischaemia-reperfusion injury
  1. R Dongworth,
  2. D M Yellon,
  3. D J Hausenloy
  1. The Hatter Cardiovascular Institute, University College London, UK

Abstract

Rationale The mitochondrial permeability transition pore (mPTP) is a critical mediator of lethal myocardial reperfusion injury. Genetic ablation of cyclophilin-D (CypD, a component of the mPTP) has been reported to acutely reduce myocardial infarct size (IS) after 2 h reperfusion. However, the role of CypD ablation in long-term cardioprotection after 72 h reperfusion has not been examined. Whether IS enlarges with increasing periods of reperfusion over 72 h, to reflect the presence of ongoing lethal myocardial reperfusion injury, is controversial.

Methodology Using B6sv129 mice, our first objective was to establish for the first time in our laboratory an in vivo recovery model of acute myocardial ischaemia-reperfusion injury (IRI) comprising 30 min occlusion of the left anterior descending (LAD) artery followed by extended reperfusion for 2, 6, 24 and 72 h. Infarct size was expressed as a % of the area-at-risk (IS/AAR%). Ischaemic preconditioning (IPC, comprising 5 min of LAD ischaemia/reperfusion prior to IRI) was used as a positive control. Mice deficient in CypD (CypD−/−) and wild-type littermates (CypD+/+) were subjected to IRI.

Results There was no increase in IS/AAR% as the reperfusion time was prolonged over the 72 h period (38.7±4.0% at 2 h, 37.3±1.7% at 6 h, 30.5±2.5% at 24 h, 33.0±4.2% at 72 h: p>0.05: N>4/group). As expected, IPC significantly reduced IS/AAR% after 72 h reperfusion (33.0±4.2% in control vs 16.2±2.7% with IPC: p<0.05: N=6/group). Mice deficient in CypD sustained smaller IS/AAR% (35.3±4.8% in CypD+/+ vs 24.3±2.0%: p=0.05: N=8/group).

Conclusions Myocardial infarct size did not enlarge with increasing duration of reperfusion. Genetic ablation of CypD confers long-term protection against IRI.

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