期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 310, 期 1, 页码 H20-H28出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00449.2015
关键词
stem cells; myocardial infarction; hypoxia
资金
- Skirball Foundation (New York, NY)
- Corbin Foundation (Akron, OH)
- American Heart Association Scientist Development Grant
The stromal cell-derived factor-1 (SDF-1): CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1: CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM-CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1 alpha requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1: CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI.
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