Abstract
AimsThe 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 resultsWild 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. ConclusionsAdministration 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.
Highlights
Myocardial infarction (MI) is a significant cause or morbidity and mortality
By quantitative RT-PCR analysis, CXCR4 expression in CM-CXCR4KO mice was found to be reduced to 37 ± 11% (N = 4; P < 0.05)
stromal derived factor-1α (SDF-1α)-CXCR4-mediated cardioprotection has been demonstrated in isolated myocytes [33], since CXCR4 is present on endothelial cells we investigated if this is important for cardioprotection in a de novo experiment
Summary
Reperfusion by primary percutaneous coronary intervention is the most effective strategy for reducing infarct size and improving clinical outcome after ST-elevation myocardial infarction (STEMI) [1,2] This is significant because infarct size in patients is known to correlate with long-term clinical outcome [3]. Despite several potential approaches to cardioprotection having been studied, and positive outcomes in several clinical trials, no approaches targeting reperfusion injury are currently used in routine clinical management [6]. Most of these previously investigated approaches have targeted cardiac myocytes directly. Novel approaches, such as those targeting the endothelium, may be more effective, either alone or in combination [7,8]
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