Stromal cell-derived factor-1 alpha signals via the endothelium to protect the heart against ischaemia-reperfusion injury

Daniel I Bromage, Stasa Taferner, Zhenhe He, Oliver J Ziff, Derek M Yellon, Sean M Davidson

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

AIMS: The chemokine stromal derived factor-1α (SDF-1α) is known to protect the heart acutely from ischaemia-reperfusion injury via its cognate receptor, CXCR4. However, the timing and cellular location of this effect, remains controversial.

METHODS AND RESULTS: Wild type male and female mice were subjected to 40 min LAD territory ischaemia in vivo and injected with either saline (control) or SDF-1α prior to 2 h reperfusion. Infarct size as a proportion of area at risk was assessed histologically using Evans blue and triphenyltetrazolium chloride. Our results confirm the cardioprotective effect of exogenous SDF-1α in mouse ischaemia-reperfusion injury and, for the first time, show protection when SDF-1α is delivered just prior to reperfusion, which has important therapeutic implications. The role of cell type was examined using the same in vivo ischaemia-reperfusion protocol in cardiomyocyte- and endothelial-specific CXCR4-null mice, and by Western blot analysis of endothelial cells treated in vitro. These experiments demonstrated that the acute infarct-sparing effect is mediated by endothelial cells, possibly via the signalling kinases Erk1/2 and PI3K/Akt. Unexpectedly, cardiomyocyte-specific deletion of CXCR4 was found to be cardioprotective per se. RNAseq analysis indicated altered expression of the mitochondrial protein co-enzyme Q10b in these mice.

CONCLUSIONS: Administration of SDF-1α is cardioprotective when administered prior to reperfusion and may, therefore, have clinical utility. SDF-1α-CXCR4-mediated cardioprotection from ischaemia-reperfusion injury is contingent on the cellular location of CXCR4 activation. Specifically, cardioprotection is mediated by endothelial signalling, while cardiomyocyte-specific deletion of CXCR4 has an infarct-sparing effect per se.

Original languageEnglish
Pages (from-to)187-197
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume128
Early online date7 Feb 2019
DOIs
Publication statusPublished - 1 Mar 2019

Keywords

  • CXCR4
  • Cardiomyocyte
  • Cardioprotection
  • Endothelial
  • Ischaemia-reperfusion injury
  • SDF-1α

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