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Hexokinase cellular trafficking in ischemia–reperfusion and ischemic preconditioning is altered in type I diabetic heart

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Abstract

Diabetes mellitus (DM) has been reported to alter the cardiac response to ischemia–reperfusion (IR). In addition, cardioprotection induced by ischemic preconditioning (IPC) is often impaired in diabetes. We have previously shown that the subcellular localisation of the glycolytic enzyme hexokinase (HK) is causally related to IR injury and IPC protective potential. Especially the binding of HK to mitochondria and prevention of HK solubilisation (HK detachment from mitochondria) during ischemia confers cardioprotection. It is unknown whether diabetes affects HK localisation during IR and IPC as compared to non-diabetes. In this study we hypothesize that DM alters cellular trafficking of hexokinase in response to IR and IPC, possibly explaining the altered response to IR and IPC in diabetic heart. Control (CON) and type I diabetic (DM) rat hearts (65 mg/kg streptozotocin, 4 weeks) were isolated and perfused in Langendorff-mode and subjected to 35 min I and 30 min R with or without IPC (3 times 5 min I). Cytosolic and mitochondrial fractions were obtained at (1) baseline, i.e. after IPC but before I, (2) 35 min I, (3) 5 min R and (4) 30 min R. DM improved rate-pressure product recovery (RPP; 71 ± 10 % baseline (DM) versus 9 ± 1 % baseline (CON) and decreased contracture (end-diastolic pressure: 24 ± 8 mmHg (DM) vs 77 ± 4 mmHg (CON)) after IR as compared to control, and was associated with prevention of HK solubilisation at 35 min I. IPC improved cardiac function in CON but not in DM hearts. IPC in CON prevented HK solubilisation at 35 min I and at 5 min R, with a trend for increased mitochondrial HK. In contrast, the non-effective IPC in DM was associated with solubilisation of HK and decreased mitochondrial HK at early reperfusion and a reciprocal behaviour at late reperfusion. We conclude that type I DM significantly altered cellular HK translocation patterns in the heart in response to IR and IPC, possibly explaining altered response to IR and IPC in diabetes.

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Acknowledgments

This study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK) (Project No: TBAG-107T212) and by Scientific Research Projects Coordination Unit of Istanbul University (Grants UDP-16146, UDP-25255).

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Authors and Affiliations

  1. Department of Biology, Faculty of Science, İstanbul University, Istanbul, Turkey

    Ebru Gurel, Savas Ustunova, Aysegul Kapucu & Cihan Demirci-Tansel

  2. Department of Biology, Faculty of Science, Namik Kemal University, Tekirdag, Turkey

    Nadim Yilmazer

  3. Department of Physiology, Academic Medical Center, Amsterdam, The Netherlands

    Otto Eerbeek

  4. Laboratory of Intensive Care and Anesthesiology, Department of Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands

    Rianne Nederlof, Markus W. Hollmann & Coert J. Zuurbier

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  1. Ebru Gurel
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Correspondence to Coert J. Zuurbier.

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Gurel, E., Ustunova, S., Kapucu, A. et al. Hexokinase cellular trafficking in ischemia–reperfusion and ischemic preconditioning is altered in type I diabetic heart. Mol Biol Rep 40, 4153–4160 (2013). https://doi.org/10.1007/s11033-013-2495-5

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  • DOI: https://doi.org/10.1007/s11033-013-2495-5

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