Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection.
Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection.
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DOI：
10.1371/journal.pone.0160889
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
McCully JD
中科院分区：
文献类型：
--
作者：
Cowan DB;Yao R;Akurathi V;Snay ER;Thedsanamoorthy JK;Zurakowski D;Ericsson M;Friehs I;Wu Y;Levitsky S;Del Nido PJ;Packard AB;McCully JD
我们以前已经表明，移植自体来源的，呼吸能力线粒体通过直接注射到心脏后短暂缺血和再灌注增强细胞活力和收缩功能。为了增加这种方法的治疗潜力，我们研究了外源性线粒体是否可以通过冠状动脉血管有效地递送以保护缺血心肌，并研究了这些移植细胞器在心脏中的命运。对Langendorff灌注的兔心脏进行30分钟的缺血，然后再灌注10分钟。用18F-罗丹明6 G和氧化铁纳米颗粒标记线粒体。将标记的线粒体直接注射到缺血区域或在再灌注开始时通过冠状动脉血管灌注递送。这些心脏用于正电子发射断层扫描，微计算机断层扫描，磁共振成像与随后的组织切片显微镜分析，以确认外源性线粒体的摄取和分布。注射的线粒体定位在递送部位附近;而线粒体的血管灌注导致在整个心脏中快速和广泛的分散。注射和灌流的线粒体都在间质中观察到，并与血管和心肌细胞相关。为了确定线粒体的血管灌注的功效，使另外一组兔心脏经受30分钟的区域缺血并再灌注120分钟。在局部缺血后，心脏立即接受通过冠状动脉输送的未标记的自体线粒体。通过冠状动脉血管灌注的自体线粒体显著减小了梗死面积，并显著增强了缺血后心肌功能。总之，通过冠状动脉输送线粒体导致其在整个心脏中的快速整合和广泛分布，并提供心脏保护免受缺血-再灌注损伤。
We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the heart. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and then reperfused for 10 minutes. Mitochondria were labeled with 18F-rhodamine 6G and iron oxide nanoparticles. The labeled mitochondria were either directly injected into the ischemic region or delivered by vascular perfusion through the coronary arteries at the onset of reperfusion. These hearts were used for positron emission tomography, microcomputed tomography, and magnetic resonance imaging with subsequent microscopic analyses of tissue sections to confirm the uptake and distribution of exogenous mitochondria. Injected mitochondria were localized near the site of delivery; while, vascular perfusion of mitochondria resulted in rapid and extensive dispersal throughout the heart. Both injected and perfused mitochondria were observed in interstitial spaces and were associated with blood vessels and cardiomyocytes. To determine the efficacy of vascular perfusion of mitochondria, an additional group of rabbit hearts were subjected to 30 minutes of regional ischemia and reperfused for 120 minutes. Immediately following regional ischemia, the hearts received unlabeled, autologous mitochondria delivered through the coronary arteries. Autologous mitochondria perfused through the coronary vasculature significantly decreased infarct size and significantly enhanced post-ischemic myocardial function. In conclusion, the delivery of mitochondria through the coronary arteries resulted in their rapid integration and widespread distribution throughout the heart and provided cardioprotection from ischemia-reperfusion injury.