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

Joseph Wider, Vishnu V.R. Undyala, Peter Whittaker, James Woods, Xuequn Chen, Karin Przyklenk

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish
Article number16
JournalBasic Research in Cardiology
Volume113
Issue number3
DOIs
StatePublished - May 1 2018

Keywords

  • Cardioprotection
  • Exosomes
  • Extracellular vesicles
  • Infarct size
  • Mass spectrometry
  • Myocardial infarction
  • Myocardial ischemia
  • Proteomics
  • Remote ischemic preconditioning
  • Type-2 diabetes

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