Centre for Clinical Pharmacology, Cardiovascular Biomedical Research Unit, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
Atherosclerosis. 2010 Nov;213(1):67-76. doi: 10.1016/j.atherosclerosis.2010.07.045. Epub 2010 Aug 4.
Adult bone marrow mononuclear cells (BMMNCs) can restore cardiac function following myocardial necrosis. Protocols used to date have administered cells relatively late after ischaemia/reperfusion injury, but there is the opportunity with elective procedures to infuse cells shortly after restoration of blood flow, for example after angioplasty. Our aim was therefore to try and quantify protection from myocardial injury by early infusion of BMMNCs in a rat ischaemia reperfusion (I/R) model.
Male Wistar rats underwent 25 min of ischaemia followed by 2 h reperfusion of the left anterior descending coronary artery. Ten million BMMNCs were injected i.v. at reperfusion. We found BMMNCs caused a significant reduction in infarct size at 2 h when assessed by staining the area at risk with p-nitro blue tetrazolium (42% reduction, P<0.01). Apoptosis and necrosis of isolated cardiomyocytes was significantly reduced in the area at risk. Functional assessment at 7 days using echocardiography and left ventricular catheterisation showed improved systolic and diastolic function in the BMMNC treatment group (LVEF: BMMNC 71 ± 3% vs. PBS 48 ± 4%, P<0.0001). In functional studies BMMNC injected animals showed increased activation of Akt, inhibition of GSK-3β, amelioration of p38 MAP kinase phosphorylation and NF-κB activity compared to control myocardium. Inhibition of PI3K with LY294002 abolished all beneficial effects of BMMNC treatment. Proteomic analysis also demonstrated that BMMNC treatment induced alterations in proteins within known cardioprotective pathways, e.g., heat shock proteins, stress-70 protein as well as the chaperone protein 14-3-3 epsilon.
Early BMMNC injection during reperfusion preserves the myocardium, with evidence of reduced apoptosis, necrosis, and activation of survival pathways.
成人骨髓单核细胞（BMMNC）可在心肌坏死后恢复心脏功能。迄今为止使用的方案是在缺血/再灌注损伤后相对较晚地给予细胞，但在择期手术中，例如在血管成形术后，有机会在血流恢复后不久输注细胞。因此，我们的目的是尝试在大鼠缺血再灌注（I / R）模型中通过早期输注 BMMNC 来量化对心肌损伤的保护作用。
雄性 Wistar 大鼠经历 25 分钟的缺血，然后再灌注左前降支冠状动脉 2 小时。在再灌注时静脉内注射 1000 万个 BMMNC。通过用 p-硝基蓝四唑（p-nitro blue tetrazolium）染色危险区域，我们发现 BMMNC 在 2 小时时导致梗塞面积显着减少（减少 42％，P<0.01）。危险区域中分离的心肌细胞的凋亡和坏死明显减少。通过超声心动图和左心室导管术在 7 天进行的功能评估显示，BMMNC 治疗组的收缩和舒张功能得到改善（LVEF：BMMNC 71±3％与 PBS 48±4％，P<0.0001）。在功能研究中，与对照心肌相比，注射 BMMNC 的动物显示 Akt 的激活增加，GSK-3β 的抑制，p38 MAP 激酶磷酸化和 NF-κB 活性的改善。用 LY294002 抑制 PI3K 消除了 BMMNC 治疗的所有有益作用。蛋白质组学分析还表明，BMMNC 处理诱导了已知的心脏保护途径中的蛋白质的改变，例如热休克蛋白，应激-70 蛋白以及伴侣蛋白 14-3-3 epsilon。
再灌注期间早期 BMMNC 注射可保护心肌，减少凋亡，坏死和生存途径的激活。
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