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Remote ischemic preconditioning fails to reduce infarct size in the Zucker fatty rat model of type-2 diabetes: role of defective humoral communication

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Abstract

Remote ischemic preconditioning (RIPC), the phenomenon whereby brief ischemic episodes in distant tissues or organs render the heart resistant to infarction, has been exhaustively demonstrated in preclinical models. Moreover, emerging evidence suggests that exosomes play a requisite role in conveying the cardioprotective signal from remote tissue to the myocardium. However, in cohorts displaying clinically common comorbidities—in particular, type-2 diabetes—the infarct-sparing effect of RIPC may be confounded for as-yet unknown reasons. To investigate this issue, we used an integrated in vivo and in vitro approach to establish whether: (1) the efficacy of RIPC is maintained in the Zucker fatty rat model of type-2 diabetes, (2) the humoral transfer of cardioprotective triggers initiated by RIPC are transported via exosomes, and (3) diabetes is associated with alterations in exosome-mediated communication. We report that a standard RIPC stimulus (four 5-min episodes of hindlimb ischemia) reduced infarct size in normoglycemic Zucker lean rats, but failed to confer protection in diabetic Zucker fatty animals. Moreover, we provide novel evidence, via transfer of serum and serum fractions obtained following RIPC and applied to HL-1 cardiomyocytes subjected to hypoxia-reoxygenation, that diabetes was accompanied by impaired humoral communication of cardioprotective signals. Specifically, our data revealed that serum and exosome-rich serum fractions collected from normoglycemic rats attenuated hypoxia-reoxygenation-induced HL-1 cell death, while, in contrast, exosome-rich samples from Zucker fatty rats did not evoke protection in the HL-1 cell model. Finally, and unexpectedly, we found that exosome-depleted serum from Zucker fatty rats was cytotoxic and exacerbated hypoxia-reoxygenation-induced cardiomyocyte death.

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Acknowledgements

JW was supported in part by NIH T32 HL120822 (Detroit Cardiovascular Training Program).

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  1. Joseph Wider

    Present address: Department of Emergency Medicine, University of Michigan, Ann Arbor, MI, USA

Authors and Affiliations

  1. Cardiovascular Research Institute, Wayne State University School of Medicine, Scott Hall, Room 4356, 540 E Canfield, Detroit, MI, 48201, USA

    Joseph Wider, Vishnu V. R. Undyala, Peter Whittaker & Karin Przyklenk

  2. Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA

    Joseph Wider, James Woods, Xuequn Chen & Karin Przyklenk

  3. Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI, USA

    Joseph Wider, Peter Whittaker & Karin Przyklenk

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  1. Joseph Wider
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  2. Vishnu V. R. Undyala
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Correspondence to Karin Przyklenk.

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Wider, J., Undyala, V.V.R., Whittaker, P. et al. Remote ischemic preconditioning fails to reduce infarct size in the Zucker fatty rat model of type-2 diabetes: role of defective humoral communication. Basic Res Cardiol 113, 16 (2018). https://doi.org/10.1007/s00395-018-0674-1

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