Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice
Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice
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DOI：
10.1152/ajpheart.00472.2006
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发表时间：
2006-11-01
影响因子：
4.8
通讯作者：
Eltzschig, Holger K.
中科院分区：
文献类型：
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作者：
Eckle, Tobias;Grenz, Almut;Eltzschig, Holger K.
缺血预适应(IP)对心脏的保护仍然是一个深入研究的领域。为了进一步阐明其分子基础，转基因小鼠的使用似乎至关重要。由于在小鼠中进行心脏IP存在技术困难，我们利用冠脉闭塞的吊重系统建立了心脏IP的原位模型。这项技术的主要优点是消除了用打结的缝线间歇性闭塞冠状动脉的必要性。为了系统地评价这一模型，我们首先证明了缺血时间(10-60分钟)与梗塞面积[3.5+/-1.3至42+/-5.2%危险面积(AAR)，伊文氏蓝/氯化三苯基四氮唑染色]之间的相关性。IP(4x5min)和冷缺血(27℃)使心肌梗死面积分别缩小69+/-6.7%和84+/-4.2%(n=6，P<；0.01)。相反，较低的IP周期数并没有改变梗塞面积。然而，来自不同遗传背景的小鼠的脑梗塞面积明显不同。除了心肌梗死染色外，我们还检测了心肌肌钙蛋白I(CTnI)作为心肌梗死的标志物。事实上，ip组小鼠血浆cTnI水平显著降低，且与梗塞面积密切相关(R2=0.8)。为了证明心脏IP的转录后果，我们从AAR中提取总RNA，并在该模型中显示IP抑制平衡的核苷转运体1-4。总而言之，这项研究证明了IP具有高度重复性的心肌梗死面积和心脏保护作用，从而最大限度地减少了与基于结节的冠状动脉闭塞模型相关的变异性。利用转基因小鼠对心脏IP的进一步研究可能会考虑这项技术。
Cardioprotection by ischemic preconditioning (IP) remains an area of intense investigation. To further elucidate its molecular basis, the use of transgenic mice seems critical. Due to technical difficulty associated with performing cardiac IP in mice, we developed an in situ model for cardiac IP using a hanging-weight system for coronary artery occlusion. This technique has the major advantage of eliminating the necessity of intermittently occluding the coronary artery with a knotted suture. To systematically evaluate this model, we first demonstrated correlation of ischemia times (10-60 min) with infarct sizes [3.5 +/- 1.3 to 42 +/- 5.2% area at risk (AAR), Evan's blue/triphenyltetrazolium chloride staining]. IP (4 x 5 min) and cold ischemia (27 degrees C) reduced infarct size by 69 +/- 6.7% and 84 +/- 4.2%, respectively (n = 6, P < 0.01). In contrast, lower numbers of IP cycles did not alter infarct size. However, infarct sizes were distinctively different in mice from different genetic backgrounds. In addition to infarct staining, we tested cardiac troponin I (cTnI) as marker of myocardial infarction in this model. In fact, plasma levels of cTnI were significantly lower in IP-treated mice and closely correlated with infarct sizes (R-2 = 0.8). To demonstrate transcriptional consequences of cardiac IP, we isolated total RNA from the AAR and showed repression of the equilibrative nucleoside transporters 1 - 4 by IP in this model. Taken together, this study demonstrates highly reproducible infarct sizes and cardiac protection by IP, thus minimizing the variability associated with knot-based coronary occlusion models. Further studies on cardiac IP using transgenic mice may consider this technique.