Letter by Loboda et al Regarding Article, “Bach1 Represses Wnt/β-Catenin Signaling and Angiogenesis”: IL-8 Is Not Present in Murine Genome Hence it Cannot Be Responsible for the Bach1 Effect on Angiogenesis in Mice

Recently, we read the article by Jiang et al 1 describing the effect exerted by Bach1 on revascularization in murine hindlimb ischemia and on angiogenic properties of murine and human endothelial cells.The authors have demonstrated, using Bach1-deficient mice that lack of this gene, encoding for an inhibitor of Nrf2 transcription factor, resulted in the enhanced perfusion and vascular density during 14 days after induction of ischemia (Figure 1A).Reversely, overexpression of Bach1 impaired blood flow restoration and angiogenesis in wild-type C57BL/6J animals.Investigating for the mechanisms of the observed changes in murine model, the authors demonstrated that lack of Bach1 is associated with increased vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) expression in ischemic muscles, as shown in Figure 1D and 1E, respectively.Similarly, in mouse lung endothelial cells isolated from Bach1 -/-mice, significant increase in IL-8 and VEGF mRNA expression was detected in comparison with cells isolated from wild-type littermates (Figure 2D).In addition, the authors showed that overexpression of Bach1 in wild-type animals decreased the expression of those growth factors respectively).Later on in the study, it was demonstrated that Bach1 regulates also the expression of VEGF and IL-8 in human endothelial cells.Accordingly, the authors concluded that diminished IL-8 and VEGF were responsible for antiangiogenic effect of Bach1.Indeed, ours 2 and others 3 studies indicated the significance of Nrf2-heme oxygenase-1 pathway in regulation of angiogenesis.As Nrf2 and heme oxygenase-1 have been demonstrated to play a proangiogenic role, 4 the antiangiogenic effect of Bach1, an inhibitor of Nrf2 activity, could be reasonably considered.In line with that was also our previous observation, cited by the authors as Reference 36 that Nrf2 regulates IL-8 expression in human endothelial cells. 5 We are, however, confused by the results from animal models showing that IL-8 is regulated (inhibited) by Bach1 and that IL-8, together with VEGF, could be a mediator of the observed effects in mouse ischemic legs.Our concern is because IL-8 is not expressed by rodent cells and it is a well-known example of so-called gene death in murine genome. 6Moreover, there is no murine ortholog of the human IL-8 gene, however, the chemokines CXCL1/KC, CXCL2/MIP-2, and CXCL5-6/LIX are regarded as functional homologs of IL-8 in rodents. 7In the commented article, the authors claim to detect murine IL-8 expression by reverse transcription polymerase chain reaction.