Published Online
on July 23, 2007

A more recent version of this article appeared on August 7, 2007

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Submitted on October 25, 2006
Accepted on May 29, 2007

Stromal Cell-Derived Factor-1 Confers Protection Against Myocardial Ischemia/Reperfusion Injury. Role of the Cardiac Stromal Cell-Derived Factor-1-CXCR4 Axis

Xiaofeng Hu MD, PhD, Shujing Dai MD, PhD, Wen-Jian Wu MSc, Wei Tan MD, Xiaoping Zhu MD, Jingyao Mu MD, Yiru Guo MD, Roberto Bolli MD, and Gregg Rokosh PhD^*

From the Institute of Molecular Cardiology, Division of Cardiology, University of Louisville, Louisville, Ky.

^* To whom correspondence should be addressed. E-mail: gregg.rokosh{at}louisville.edu.

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 (P<0.05). 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 (P<0.05) 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) (P<0.05). 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 (P<0.05). 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 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.

Key words: CXCL12 chemokine • CXCR4 protein, mouse • ischemia • myocardial infarction • reperfusion

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