Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1496-505. doi: 10.1152/ajpheart.00365.2011. Epub 2011 Aug 5.
Stromal cell-derived factor-1α (SDF-1) has been reported to mediate cardioprotection through the mobilization of stem cells into injured tissue and an increase in local angiogenesis after myocardial infarction. However, little is known regarding whether SDF-1 induces acute protection following global myocardial ischemia/reperfusion (I/R) injury and if so, by what molecular mechanism. SDF-1 binding to its cognate receptor CXCR4 has been shown to activate STAT3 in a variety of cells. STAT3 is a cardioprotective factor and may mediate SDF-1/CXCR4-induced acute protection. We hypothesized that SDF-1 would improve myocardial function through CXCR4-increased STAT3 activation following acute I/R. Isolated mouse hearts were subjected to 25-min global ischemia/40-min reperfusion and divided into groups of 1) vehicle; 2) SDF-1; 3) AMD3100, a CXCR4 inhibitor; 4) SDF-1 + AMD3100; 5) Stattic, a STAT3 inhibitor; 6) SDF-1 + Stattic; 7) cardiomyocyte-restricted ablation of STAT3 (STAT3KO); 8) STAT3KO + SDF-1; 9) Ly294002, an inhibitor of the Akt pathway; and 10) SDF-1 + Ly294002. Reagents were infused into hearts within 5 min before ischemia. SDF-1 administration significantly improved postischemic myocardial functional recovery in a dose-dependent manner. Additionally, pretreatment with SDF-1 reduced cardiac apoptotic signaling and increased myocardial STAT3 activation following acute I/R. Inhibition of the SDF-1 receptor CXCR4 neutralized these protective effects by SDF-1 in hearts subjected to I/R. Notably, inhibition of the STAT3 pathway or use of STAT3KO hearts abolished SDF-1-induced acute protection following myocardial I/R. Our results represent the first evidence that the SDF-1/CXCR4 axis upregualtes myocardial STAT3 activation and, thereby, mediates acute cardioprotection in response to global I/R.
基质细胞衍生因子-1α（SDF-1）已被报道通过动员干细胞进入损伤组织并增加心肌梗死后局部血管生成来介导心脏保护。然而，对于 SDF-1 是否在心肌全缺血/再灌注（I/R）损伤后立即引起急性保护作用以及如果是，其通过什么分子机制尚不清楚。SDF-1 与其同源受体 CXCR4 的结合已被证明可在多种细胞中激活 STAT3。STAT3 是一种心脏保护因子，可能介导 SDF-1/CXCR4 诱导的急性保护作用。我们假设 SDF-1 通过急性 I/R 后 CXCR4 增加的 STAT3 激活来改善心肌功能。分离的小鼠心脏经历 25 分钟的全缺血/40 分钟的再灌注，并分为以下几组：1）载体；2）SDF-1；3）AMD3100，一种 CXCR4 抑制剂；4）SDF-1 + AMD3100；5）Stattic，一种 STAT3 抑制剂；6）SDF-1 + Stattic；7）心肌细胞特异性 STAT3 消融（STAT3KO）；8）STAT3KO + SDF-1；9）Ly294002，一种 Akt 通路抑制剂；和 10）SDF-1 + Ly294002。在缺血前 5 分钟内将试剂输注到心脏中。SDF-1 的给药以剂量依赖性方式显著改善缺血后的心肌功能恢复。此外，急性 I/R 后，SDF-1 的预处理可减少心脏凋亡信号并增加心肌 STAT3 激活。SDF-1 受体 CXCR4 的抑制消除了 I/R 心脏中 SDF-1 的这些保护作用。值得注意的是，STAT3 通路的抑制或使用 STAT3KO 心脏消除了 SDF-1 诱导的心肌 I/R 后的急性保护作用。我们的结果代表了第一个证据，即 SDF-1/CXCR4 轴上调心肌 STAT3 激活，并因此介导对全 I/R 的急性心脏保护作用。
