Role of the Cardiac Stromal Cell–Derived Factor-1–CXCR4 Axis

Background—Stromal cell–derived factor-1 (SDF-1) 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–CXCR4 axis in modulating myocardial ischemia/reperfusion injury is unknown. Methods and Results—In mice subjected to ischemic preconditioning, myocardial SDF-1 mRNA was found to be increased 3 hours later (P0.05). Myocardial SDF-1 and CXCR4 mRNA and protein were found to be expressed in both cardiac myocytes and fibroblasts. SDF-1 production increased significantly after 1 or 4 hours of hypoxia and 18 hours of reoxygenation in cultured myocytes (P0.05) but did not change in fibroblast cultures. In isolated myocytes, CXCR4 activation by SDF-1 resulted in increased phosphorylation of both ERK 1/2 and AKT and decreased phosphorylation of JNK and p38. Cultured myocytes pretreated with SDF-1 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) (P0.05). This protective effect was blocked by the CXCR4 selective antagonist AMD3100. In vivo, administration of SDF-1 before 30 minutes of coronary occlusion followed by 4 hours of reperfusion decreased infarct size (P0.05). The decrease in infarct size with SDF-1 administration also was blocked by AMD3100. Conclusions—We conclude that SDF-1 and its receptor, CXCR4, constitute a paracrine or autocrine axis in cardia