P137Cyclophilin-D ablation offers long-term protection against lethal myocardial reperfusion injury

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Abstract

Purpose

Lethal myocardial reperfusion injury attenuates the benefits of myocardial reperfusion following an acute myocardial infarction in terms of myocardial salvage. The opening of the mitochondrial permeability transition pore (mPTP) at the onset of reperfusion is a major contributor of lethal myocardial reperfusion injury. Genetic ablation of cyclophilin-D (CypD, a component of the mPTP) has been reported to reduce myocardial infarct size (IS) after 2hrs reperfusion. However, the role of CypD ablation in long-term cardioprotection after 72hrs reperfusion has not been examined. Whether lethal myocardial reperfusion injury progresses with increasing periods of reperfusion is controversial, and is also investigated here.

Methods

Using B6sv129 male 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 30min occlusion of the left anterior descending (LAD) artery followed by extended reperfusion for 2, 6, 24 and 72hrs. Infarct size was expressed as a % of the area-at-risk (IS/AAR%). Ischaemic preconditioning (IPC, comprising one-5 min cycle of LAD occlusion and reflow 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 72hr period (38.4 ± 3.4% at 2hrs, 37.4 ± 1.4% at 6hrs, 31.4 ± 3.5% at 24hrs, 32.0 ± 3.7% at 72hrs:P > 0.05:N > 7/group). As expected, IPC significantly reduced IS/AAR% after 72hrs reperfusion (32.0 ± 3.7% in control versus 16.2 ± 2.7% with IPC:P < 0.05:N=6/group). Male mice deficient in CypD sustained smaller IS/AAR% (35.4 ± 4.3% in male CypD + / + versus 22.6 ± 2.4% in male CypD -/-:P < 0.05:N=9/group). Similar results were also observed in female mice deficient in CypD (39.7 ± 5.4% in female CypD + / + versus 24.7 ± 3.5% in female CypD -/-:P < 0.05:N=7/group).

Conclusions

Myocardial infarct size did not enlarge with increasing duration of reperfusion suggesting that in the murine model lethal myocardial reperfusion injury does not progress over time. Genetic ablation of CypD confers long-term protection against IRI in both male and female mice.

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