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

• Published in: Journal of molecular and cellular cardiology Vol. 128; pp. 187 - 197
• Main Authors: Bromage, Daniel I., Taferner, Stasa, He, Zhenhe, Ziff, Oliver J., Yellon, Derek M., Davidson, Sean M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2019; Academic Press
• Subjects: Animals; Cardiomyocyte; Cardioprotection; Chemokine CXCL12 - genetics; Chemokine CXCL12 - pharmacokinetics; CXCR4; Disease Models, Animal; Endothelial; Endothelium - drug effects; Endothelium - pathology; Heart - drug effects; Heart - physiopathology; Humans; Ischaemia-reperfusion injury; Mice; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Original; Protective Agents; Receptors, CXCR4 - genetics; Reperfusion Injury - genetics; Reperfusion Injury - pathology; Reperfusion Injury - therapy; SDF-1α; Signal Transduction - drug effects; Endothelial; SDF-1α; CXCR4; Ischaemia-reperfusion injury; Cardioprotection; Cardiomyocyte
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2019.02.002

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. 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. 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. •SDF-1α protects against ischaemia-reperfusion injury, but the mechanism is unknown.•Exogenous SDF-1α is protective when delivered just prior to reperfusion.•The acute infarct-sparing effect appears to be mediated by endothelial cells.•Cardiomyocyte-specific deletion of CXCR4 was found to be cardioprotective per se.