Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Am J Physiol Heart Circ Physiol. 2013 Apr 1;304(7):H966-82. doi: 10.1152/ajpheart.00883.2012. Epub 2013 Jan 25.
Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 ± 1.7 × 10(6)/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased (P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI-mitochondria (7.9 ± 2.9%) compared with RI-vehicle (34.2 ± 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2-8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high-energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury.
线粒体损伤和功能障碍发生在缺血期间，并在再灌注期间显著调节心脏功能和细胞存活。我们假设，在再灌注之前立即移植自体衍生的线粒体将改善这些效果。新西兰白兔用于区域缺血（RI），通过暂时套住左前降支 30 分钟来实现。在 RI 30 分钟后，将自体衍生的线粒体（RI-线粒体；9.7±1.7×10（6）/ml）或单独的载体（RI-载体）直接注射到 RI 区，然后让心脏恢复 4 周。线粒体移植显著降低（P<0.05）RI 区肌酸激酶 MB、心肌肌钙蛋白-I 和细胞凋亡。在 4 周的恢复后，RI-线粒体的梗死面积明显减少（7.9±2.9%），而 RI-载体的梗死面积明显增加（34.2±3.3%，P<0.05）。连续超声心动图显示，RI-线粒体心脏在再灌注开始后 10 分钟内恢复正常收缩；然而，RI-载体心脏在 4 周的恢复时，RI 区仍表现出持续的运动减退。心电图和光学映射研究表明，自体衍生的线粒体移植与心律失常无关。体内和体外研究表明，移植的线粒体在间质空间中是明显的，并在移植后 2-8 小时被心肌细胞内化。移植的线粒体增强了氧消耗、高能磷酸合成以及细胞因子介质和蛋白质组学途径的诱导，这些途径对维持心肌能量代谢、细胞活力和增强梗死后心功能至关重要。自体衍生的线粒体移植为保护心脏免受缺血再灌注损伤提供了一种新的技术。
