Stromal cell-derived factor-1α confers protection against myocardial ischemia/reperfusion injury -: Role of the cardiac stromal cell-derived factor-1α-CXCR4 axis

Background - Stromal cell-derived factor-1 alpha (SDF-1 alpha) binding to its cognate receptor, CXCR4, regulates a variety of cellular functions such as stem cell homing, trafficking, and differentiation. However, the role of the SDF-1 alpha-CXCR4 axis in modulating myocardial ischemia/ reperfusion injury is unknown. Methods and Results - In mice subjected to ischemic preconditioning, myocardial SDF-1 alpha mRNA was found to be increased 3 hours later (P < 0.05). Myocardial SDF-1 alpha and CXCR4 mRNA and protein were found to be expressed in both cardiac myocytes and fibroblasts. SDF-1 alpha production increased significantly after 1 or 4 hours of hypoxia and 18 hours of reoxygenation in cultured myocytes (P < 0.05) but did not change in fibroblast cultures. In isolated myocytes, CXCR4 activation by SDF-1 alpha resulted in increased phosphorylation of both ERK 1/2 and AKT and decreased phosphorylation of JNK and p38. Cultured myocytes pretreated with SDF-1 alpha were resistant to hypoxia/reoxygenation damage, exhibiting less lactate dehydrogenase release, trypan blue uptake, and apoptotic cell death (terminal deoxynucleotidyl transferase-mediated dUTP nick- end labeling assay) (P < 0.05). This protective effect was blocked by the CXCR4 selective antagonist AMD3100. In vivo, administration of SDF-1 alpha before 30 minutes of coronary occlusion followed by 4 hours of reperfusion decreased infarct size (P < 0.05). The decrease in infarct size with SDF-1 alpha administration also was blocked by AMD3100. Conclusions - We conclude that SDF-1 alpha and its receptor, CXCR4, constitute a paracrine or autocrine axis in cardiac myocytes that is activated in response to preconditioning and hypoxic stimuli, recruiting the antiapoptotic kinases ERK and AKT and promoting an antiapoptotic program that confers protection against ischemia/ reperfusion damage.