Gene dosage-dependent effects of cardiac-specific overexpression of the A3 adenosine receptor
Gene dosage-dependent effects of cardiac-specific overexpression of the A3 adenosine receptor
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DOI：
10.1161/01.res.0000028007.91385.ee
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发表时间：
2002-07-26
影响因子：
20.1
通讯作者：
Auchampach, JA
中科院分区：
文献类型：
--
作者：
Black, RG;Guo, YR;Auchampach, JA
我们采用一种遗传学方法来确定心脏中表达的A(3)腺苷受体（A(3)ARs）水平升高是否能在不引发心脏病变的情况下对缺血起到保护作用。我们培育出携带1个（A(3)tg.1）或6个（A(3)tg.6）转基因拷贝的小鼠，该转基因由心肌细胞特异性α -肌球蛋白重链基因启动子和A(3)AR cDNA组成。A(3)tg.1和A(3)tg.6小鼠在心肌中分别表达12.7 ± 3.15和66.3 ± 9.4飞摩尔/毫克的高亲和力G蛋白偶联形式的A(3)AR。广泛的形态学、组织学和功能分析表明，与非转基因小鼠相比，A(3)tg.1转基因小鼠没有明显异常。相比之下，A(3)tg.6小鼠表现出心脏扩张、肥大标志物表达、心动过缓、低血压和收缩功能障碍。当A(3)tg小鼠经历30分钟的冠状动脉闭塞和24小时的再灌注时，与非转基因同窝小鼠相比，A(3)tg.1小鼠的梗死面积减少了约30%，A(3)tg.6小鼠的梗死面积减少了约40%。转基因小鼠梗死面积的减少与危险区域大小、全身血流动力学或体温的差异无关，这表明心脏保护作用是缺血心肌中A(3)AR信号增强的结果。结果表明，心脏中A(3)AR的低水平表达可有效保护免受缺血性损伤，且无明显不良影响，而较高水平的A(3)AR表达则会导致扩张型心肌病的发生。
We used a genetic approach to determine whether increasing the level of A(3) adenosine receptors (A(3)ARs) expressed in the heart confers protection against ischemia without causing cardiac pathology. We generated mice carrying one (A(3)tg.1) or six (A(3)tg.6) copies of a transgene consisting of the cardiomyocyte-specific alpha-myosin heavy chain gene promoter and the A(3)AR cDNA. A(3)tg.1 and A(3)tg.6 mice expressed 12.7 +/- 3.15 and 66.3 +/- 9.4 fmol/mg of the high-affinity G protein-coupled form of the A(3)AR in the myocardium, respectively. Extensive morphological, histological, and functional analyses demonstrated that there were no apparent abnormalities in A(3)tg.1 transgenic mice compared with nontransgenic mice. In contrast, A(3)tg.6 mice exhibited dilated hearts, expression of markers of hypertrophy, bradycardia, hypotension, and systolic dysfunction. When A(3)tg mice were subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion, infarct size was reduced approximate to30% in A(3)tg.1 mice and approximate to40% in A(3)tg.6 mice compared with nontransgenic littermates. The reduction in infarct size in the transgenic mice was not related to differences in risk region size, systemic hemodynamics, or body temperature, indicating that the cardioprotection was a result of increased A(3)AR signaling in the ischemic myocardium. The results demonstrate that low-level expression of A(3)ARs in the heart provides effective protection against ischemic injury without detectable adverse effects, whereas higher levels of A(3)AR expression lead to the development of a dilated cardiomyopathy.