Abstract | BACKGROUND: METHODS AND RESULTS: In mice subjected to ischemic preconditioning, myocardial SDF-1alpha mRNA was found to be increased 3 hours later (P<0.05). Myocardial SDF-1alpha and CXCR4 mRNA and protein were found to be expressed in both cardiac myocytes and fibroblasts. SDF-1alpha 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-1alpha resulted in increased phosphorylation of both ERK 1/2 and AKT and decreased phosphorylation of JNK and p38. Cultured myocytes pretreated with SDF-1alpha 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-1alpha 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-1alpha administration also was blocked by AMD3100. CONCLUSIONS: We conclude that SDF-1alpha 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.
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Authors | Xiaofeng Hu, Shujing Dai, Wen-Jian Wu, Wei Tan, Xiaoping Zhu, Jingyao Mu, Yiru Guo, Roberto Bolli, Gregg Rokosh |
Journal | Circulation
(Circulation)
Vol. 116
Issue 6
Pg. 654-63
(Aug 07 2007)
ISSN: 1524-4539 [Electronic] United States |
PMID | 17646584
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Chemokine CXCL12
- Chemokines, CXC
- Cxcl12 protein, mouse
- Receptors, CXCR4
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Topics |
- Animals
- Cell Survival
(physiology)
- Cells, Cultured
- Chemokine CXCL12
- Chemokines, CXC
(physiology)
- Hypoxia
(metabolism, pathology)
- Ischemic Preconditioning, Myocardial
(methods)
- Male
- Mice
- Mice, Inbred C57BL
- Myocardial Ischemia
(metabolism, prevention & control)
- Myocardial Reperfusion Injury
(metabolism, prevention & control)
- Myocytes, Cardiac
(physiology)
- Paracrine Communication
(physiology)
- Rats
- Receptors, CXCR4
(biosynthesis, physiology)
- Stromal Cells
(metabolism, physiology)
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