Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction
Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction
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DOI：
10.1152/ajpheart.00741.2001
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发表时间：
2002-03-01
影响因子：
4.8
通讯作者：
Matherne, GP
中科院分区：
文献类型：
--
作者：
Yang, ZQ;Cerniway, RJ;Matherne, GP
先前的研究表明，在转基因（TG）小鼠中高水平（300倍正常）的心脏A（1）-腺苷受体（A（1）-AR）过表达可保护离体心脏免受缺血-再灌注损伤。然而，这种高水平的过表达与心动过缓和完整小鼠缺血期间心律失常的发生率增加有关，这干扰了确定该品系TG小鼠是否也可以在体内免受心肌梗死（MI）的研究。因此，在这些研究中，我们选择了一种TG小鼠品系，其A（1）-AR以更适度的水平（正常的30倍）过表达，这在离体心脏中提供心脏保护，同时在完整小鼠中缺血期间最小化心动过缓和心律失常。野生型（WT; n = 10）和中等水平的A（1）-AR TG（n = 10）小鼠进行45分钟的冠状动脉左前降支闭塞，随后再灌注24小时。分别通过氯化三苯基四氮唑和酞蓝染色确定肿瘤大小和危险区域。WT小鼠的脑梗死面积为52 ± 3%，而TG小鼠中A（1）-ARs的过表达显著降低了梗死面积至31 ± 3%（P < 0.05）。此外，心肌梗死后24小时通过心脏磁共振成像测定的收缩功能（左心室射血分数）在TG与WT小鼠中得到更好的保留。心脏过表达A（1）-ARs可使心肌梗死面积减少40%，并保护心肌梗死后的心脏功能。
Previous studies have shown that high-level (300-fold normal) cardiac overexpression of A(1)-adenosine receptors (A(1)-ARs) in transgenic (TG) mice protects isolated hearts against ischemia-reperfusion injury. However, this high level of overexpression is associated with bradycardia and increased incidence of arrhythmia during ischemia in intact mice, which interfered with studies to determine whether this line of TG mice might also be protected against myocardial infarction (MI) in vivo. For these studies, we therefore selected a line of TG mice that overexpresses the A(1)-AR at more moderate levels (30-fold normal), which affords cardioprotection in the isolated heart while minimizing bradycardia and arrhythmia during ischemia in intact mice. Wild-type (WT; n = 10) and moderate-level A(1)-AR TG (n = 10) mice underwent 45 min of left anterior descending coronary artery occlusion, followed by 24-h reperfusion. Infarct size and region at risk were determined by triphenyltetrazolium chloride and phthalo blue staining, respectively. Infarct size (% region at risk) in WT mice was 52 +/- 3%, whereas overexpression of A(1)-ARs in the TG mice markedly reduced infarct size to 31 +/- 3% (P < 0.05). Furthermore, contractile function (left ventricular ejection fraction) as determined by cardiac magnetic resonance imaging 24 h after MI was better preserved in TG vs. WT mice. Cardiac overexpression of A(1)-ARs reduces infarct size by 40% and preserves cardiac function in intact mice after MI.