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Abstract
Background We have recently demonstrated that stromal cell-derived factor 1α (SDF-1α) limits myocardial infarct size (IS) in a murine model of ischaemia-reperfusion injury (IRI) via its receptor CXCR4. This study aimed to investigate the role of SDF-1α in the cardioprotection conferred by remote ischaemic conditioning (RIC) using three different human and animal models.
Methods 1) In vivo RIC: Rats were anaesthetised with sodium pentobarbitone (60mg/kg i.p.), intubated and ventilated. Animals were randomly allocated to receive intravenously either a specific inhibitor of CXCR4, AMD3100 (10µg/ml), or vehicle (0.9% saline). Animals then underwent either a RIC protocol (3 × 5 min hind limb ischaemia) or a sham procedure for the same time period. Complete cessation of blood flow in the RIC group was confirmed by Doppler measurement. All groups were subjected to 30 min left coronary artery occlusion and 2h reperfusion (IR), after which the heart was removed and analysed for IS as a proportion of area at risk (IS/AAR%). 2) Ex vivo RIC: Coronary effluent was collected from isolated perfused rat hearts following either stabilisation (Ceff) or during a preconditioning protocol (3 × 5 min, IPCeff). Recipient hearts were perfused with effluent for 10 min (± 5 µg/ml AMD) prior to 35 min LCA occlusion and 60 min reperfusion. Infarct size was measured as above. 3) Isolated human atrial muscle: Trabeculae isolated from right atrial appendage tissue were harvested during cardiac surgery. All samples were subjected to 60 min hypoxia and 60 min reoxygenation. Samples were randomised to four groups: (1) Control; (2) SDF-1α (25ng/ml) for 30 min prior to hypoxia; (3) AMD3100 (10µg/ml) + SDF-1α (25ng/ml), AMD3100 for 10 min prior to SDF-1α; (4) AMD3100 (10µg/ml) 40 min prior to hypoxia. Recovery of contractile function (% recovery compared to baseline) was assessed after 60 min reoxygenation.
Results (1) RIC significantly reduced IS in vivo from 57 ± 3% to 31 ± 4% (N = 6 and 5 respectively, p < 0.05 vs IR + vehicle). This cardioprotection was abrogated by the addition of AMD3100 (57 ± 5%, N=5, p > 0.05 vs RIC+vehicle). AMD3100 alone had no significant effect on IS (62 ± 2%, N=6, p > 0.05 vs IR+vehicle). (2) IPCeff significantly reduced IS in isolated hearts from 41 ± 5% (Ceff) to 22 ± 6% (N=7, p < 0.05). However, AMD3100 did not inhibit IPCeff mediated cardioprotection (25 ± 2%, p > 0.05 vs IPCeff). (3) SDF-1α significantly improved % recovery of human atrial trabeculae subjected to simulated IRI from 28 ± 2% (control) to 52 ± 2% (N=10, p < 0.05). This protection was significantly reduced by pre-treatment with AMD3100 (SDF-1α 52 ± 2% vs AMD3100+SDF-1α 28 ± 2% [N=7]; p < 0.05). AMD3100 alone did not affect recovery (AMD3100 30 ± 4% vs C, p > 0.05).
Conclusion This study suggests that SDF-1α is a mediator of RIC. It appears to be produced remote from the heart and exert its actions on the myocardium via activation of the CXCR4 receptor.
- Remote ischaermic conditoning
- Stromal cell derived factor 1a
- Human atrial trabeculae