TY - JOUR
T1 - Stromal cell-derived factor-1α confers protection against myocardial ischemia/reperfusion injury
T2 - Role of the cardiac stromal cell-derived factor-1α-CXCR4 axis
AU - Hu, Xiaofeng
AU - Dai, Shujing
AU - Wu, Wen Jian
AU - Tan, Wei
AU - Zhu, Xiaoping
AU - Mu, Jingyao
AU - Guo, Yiru
AU - Bolli, Roberto
AU - Rokosh, Gregg
PY - 2007/8
Y1 - 2007/8
N2 - BACKGROUND - Stromal cell-derived factor-1α (SDF-1α) 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-1α-CXCR4 axis in modulating myocardial ischemia/reperfusion injury is unknown. METHODS AND RESULTS - In mice subjected to ischemic preconditioning, myocardial SDF-1α mRNA was found to be increased 3 hours later (P<0.05). Myocardial SDF-1α and CXCR4 mRNA and protein were found to be expressed in both cardiac myocytes and fibroblasts. SDF-1α 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-1α resulted in increased phosphorylation of both ERK 1/2 and AKT and decreased phosphorylation of JNK and p38. Cultured myocytes pretreated with SDF-1α 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-1α 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-1α administration also was blocked by AMD3100. CONCLUSIONS - We conclude that SDF-1α 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.
AB - BACKGROUND - Stromal cell-derived factor-1α (SDF-1α) 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-1α-CXCR4 axis in modulating myocardial ischemia/reperfusion injury is unknown. METHODS AND RESULTS - In mice subjected to ischemic preconditioning, myocardial SDF-1α mRNA was found to be increased 3 hours later (P<0.05). Myocardial SDF-1α and CXCR4 mRNA and protein were found to be expressed in both cardiac myocytes and fibroblasts. SDF-1α 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-1α resulted in increased phosphorylation of both ERK 1/2 and AKT and decreased phosphorylation of JNK and p38. Cultured myocytes pretreated with SDF-1α 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-1α 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-1α administration also was blocked by AMD3100. CONCLUSIONS - We conclude that SDF-1α 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.
KW - CXCL12 chemokine
KW - CXCR4 protein, mouse
KW - Ischemia
KW - Myocardial infarction
KW - Reperfusion
UR - http://www.scopus.com/inward/record.url?scp=34548174756&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.106.672451
DO - 10.1161/CIRCULATIONAHA.106.672451
M3 - Article
C2 - 17646584
AN - SCOPUS:34548174756
SN - 0009-7322
VL - 116
SP - 654
EP - 663
JO - Circulation
JF - Circulation
IS - 6
ER -