Lin Jih-Shyong, Chen Yih-Sharng, Chiang Han-Sun, Ma Ming-Chieh
School of Medicine, Fu Jen Catholic University, 510 Chungcheng Road, Hsinchuang 242, Taiwan.
J Physiol. 2008 Dec 1;586(23):5757-69. doi: 10.1113/jphysiol.2008.160887. Epub 2008 Oct 9.
Preconditioning, such as by brief hypoxic exposure, has been shown to protect hearts against severe ischaemia. Here we hypothesized that hypoxic preconditioning (HPC) protects injured hearts by mobilizing the circulating progenitor cells. Ischaemia-reperfusion (IR) injury was induced by left coronary ligation and release in rats kept in room air or preconditioned with 10% oxygen for 6 weeks. To study the role of erythropoietin (EPO), another HPC + IR group was given an EPO receptor (EPOR) antibody via a subcutaneous mini-osmotic pump 3 weeks before IR induction. HPC alone gradually increased haematocrit, cardiac and plasma EPO, and cardiac vascular endothelial growth factor (VEGF) only in the first two weeks. HPC improved heart contractility, reduced ischaemic injury, and maintained EPO and EPOR levels in the infarct tissues of IR hearts, but had no significant effect on VEGF. Interestingly, the number of CD34(+)CXCR4(+) cells in the peripheral blood and their expression in HPC-treated hearts was higher than in control. Preconditioning up-regulated cardiac expression of stromal derived factor-1 (SDF-1) and prevented its IR-induced reduction. The EPOR antibody abolished HPC-mediated functional recovery, and reduced SDF-1, CXCR4 and CD34 expression in IR hearts, as well as the number of CD34(+)CXCR4(+) cells in blood. The specificity of neutralizing antibody was confirmed in an H9c2 culture system. In conclusion, exposure of rats to moderate hypoxia leads to an increase in progenitor cells in the heart and circulation. This effect is dependent on EPO, which induces cell homing by increased SDF-1/CXCR4 and reduces the heart susceptibly to IR injury.
预处理，如通过短暂的低氧暴露，已被证明可保护心脏免受严重缺血的影响。在此，我们假设低氧预处理（HPC）通过动员循环祖细胞来保护受损心脏。在置于室内空气中或用10%氧气预处理6周的大鼠中，通过左冠状动脉结扎和松开诱导缺血再灌注（IR）损伤。为了研究促红细胞生成素（EPO）的作用，另一个HPC + IR组在IR诱导前3周通过皮下微型渗透泵给予EPO受体（EPOR）抗体。单独的HPC仅在前两周逐渐增加血细胞比容、心脏和血浆EPO以及心脏血管内皮生长因子（VEGF）。HPC改善了心脏收缩力，减少了缺血损伤，并维持了IR心脏梗死组织中的EPO和EPOR水平，但对VEGF没有显著影响。有趣的是，外周血中CD34(+)CXCR4(+)细胞的数量及其在HPC处理心脏中的表达高于对照组。预处理上调了心脏基质衍生因子-1（SDF-1）的表达，并防止其因IR而降低。EPOR抗体消除了HPC介导的功能恢复，并降低了IR心脏中SDF-1、CXCR4和CD34的表达，以及血液中CD34(+)CXCR4(+)细胞的数量。在H9c2培养系统中证实了中和抗体的特异性。总之，大鼠暴露于中度低氧会导致心脏和循环中祖细胞增加。这种效应依赖于EPO，EPO通过增加SDF-1/CXCR4诱导细胞归巢，并降低心脏对IR损伤的易感性。
