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Remote Cardioprotection by Transfer of Coronary Effluent from Ischemic Preconditioned Rabbit Heart Preserves Mitochondrial Integrity and Function via Adenosine Receptor Activation

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Abstract

Background

Coronary effluent from an isolated perfused heart undergoing ischemic preconditioning can be transferred to precondition another naïve isolated heart. We investigated the effects of this effluent on mitochondrial integrity and function following a global infarct model of ischemia/reperfusion and the role of adenosine in this model of remote preconditioning.

Methods and Results

Coronary effluent from isolated perfused rabbit hearts was collected prior to (control effluent) and during three cycles of 5-min ischemia and 10-min reperfusion (IPC effluent). Adenosine concentration was significantly increased in IPC effluent (2.6 ± 1.1 μM) versus control effluent (0.21 ± 0.06 μM, P < 0.01). Infarct size (% necrotic LV mass) after 30-min global ischemia and 90-min reperfusion was significantly reduced in hearts preconditioned with IPC effluent (IPCeff, 23 ± 7 %) and control effluent supplemented with 2.5 μM exogenous adenosine (Ceff + 2.5 μM ADO, 25 ± 10 %) when compared to control effluent perfused hearts (Ceff, 41 ± 8 %, P < 0.05). Compared to Ceff mitochondria, IPCeff mitochondria had preserved complex I/State3 and complex IV/State 3 respiration and outer membrane integrity, and reduced cytochrome c release. In contrast, Ceff + 2.5 μM ADO mitochondria had improved state 2 respiration and coupling to oxidative phosphorylation, reduced reactive oxygen species production and preserved outer membrane integrity. Administration of adenosine receptor blocker 8-(p-sulfophenyl)theophylline abolished the infarct limiting effect (46 ± 7 %) and the mitochondrial integrity and function preservation of IPC effluent.

Conclusion

Remote cardioprotection by IPC effluent preserves mitochondrial integrity and function in an adenosine receptor dependent mechanism, and although infarct size reduction can be mimicked by adenosine, IPC effluent contains additional factor(s) contributing to modulation of the mitochondrial response to ischemia/reperfusion injury.

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Grants

This study was supported by The Leducq Foundation (grant number 06/CVD) and the Heart and Stroke Foundation of Ontario.

Conflicts of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Cardiovascular Surgery, Hospital for Sick Children/University of Toronto, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8

    Chung Ho Leung, Lixing Wang, Yana Y. Fu, Hideyuki Kato & Christopher A. Caldarone

  2. Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, Denmark

    Jan M. Nielsen

  3. Division of Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada

    Michael B. Tropak & John Callahan

  4. Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada

    Andrew N. Redington

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  1. Chung Ho Leung
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Correspondence to Christopher A. Caldarone.

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Supplementary Figure 1

Ions detected in the effluent by reverse phase liquid chromatography mass spectrometry. Intensity of select ions in IPC effluent (n = 2) relative to Control effluent (n = 2) is shown on the y-axis. Mass to charge (m/z) ratio for detected ions are shown on the x-axis. This ratio is a reflection of the molecular weight of the individual ions detected by the mass spectrometer (LTQ Orbitrap). (JPEG 12 kb)

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Leung, C.H., Wang, L., Nielsen, J.M. et al. Remote Cardioprotection by Transfer of Coronary Effluent from Ischemic Preconditioned Rabbit Heart Preserves Mitochondrial Integrity and Function via Adenosine Receptor Activation. Cardiovasc Drugs Ther 28, 7–17 (2014). https://doi.org/10.1007/s10557-013-6489-2

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