Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase
Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase
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DOI：
10.1016/j.cardfail.2006.03.002
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发表时间：
2006-06-01
影响因子：
6
通讯作者：
Jay, PY
中科院分区：
文献类型：
--
作者：
Buerger, A;Rozhitskaya, O;Jay, PY
背景：利用P1Cre-loxP重组噬菌体系统进行小鼠条件性基因失活需要组织特异性启动子或诱导启动子驱动Cre-重组酶的转基因表达。方法和结果：利用最常用的心肌特异性转基因启动子--心肌α-肌球蛋白重链启动子，我们建立了在心脏表达Cre-重组酶的转基因小鼠。七个转基因株系出现扩张型心肌病和充血性心力衰竭导致的过早死亡。一个存活了足够长时间以进行繁殖的创始人株系具有极高水平的Cre重组酶表达。低水平表达的转基因株系仍然健康。这种高表达菌株在非常可预测和可重复性的时间过程中发展为心力衰竭。对高表达菌株的详细检查揭示了心肌病的重要分子、细胞和药理学特征。首先，“胎儿基因”如心房利钠因子和脑利钠蛋白被表达，这是病理性心肌肥大和心力衰竭的标志。其次，心肌细胞凋亡的发生率增加。第三，用卡托普利或美托洛尔治疗小鼠，可以延缓心力衰竭的进展，提高存活率。结论：Cre重组酶在高水平表达时可能导致器官功能障碍，这可能被误认为是条件性基因失活的影响。此外，在具有特征的、高表达的转基因菌株中的刻板印象的心肌病和疾病进展表明，它作为研究药物或遗传操作在心力衰竭中的作用的模型是有用的。
Background: Conditional gene inactivation in mice using the bacteriophage P1 Cre-loxP recombination system requires transgenic expression of Cre-recombinase driven by a tissue-specific or inducible promoter.Methods and Results: Using the cardiac alpha-myosin-heavy-chain promoter, the most commonly used myocardial-specific transgenic promoter, we created transgenic mice expressing Cre-recombinase in the heart. Seven transgenic lines developed dilated cardiomyopathy and premature death from congestive heart failure. One founder line that survived long enough to propagate had extremely high-level Cre recombinase expression. Transgenic lines that expressed low levels remained healthy. The high-expressing strain developed heart failure over a very predictable and reproducible time course. Detailed examination of the high-expressing strain revealed important molecular, cellular, and pharmacologic hallmarks of cardiomyopathy. First, "fetal genes" such as atrial natriuretic factor and brain natriuretic protein were expressed, a marker of pathologic cardiac hypertrophy and heart failure. Second, an increased incidence of cardiac myocyte apoptosis was present. Third, treatment of mice with captopril or metoprolol, drugs that delay the progression of heart failure, improved survival.Conclusion: Cre-recombinase when expressed at high levels may cause organ dysfunction, which could be mistaken for an effect of conditional gene inactivation. In addition, the stereotypic cardiomyopathy and disease progression in the characterized, high-expressing transgenic strain suggests its utility as a model to study the effects of pharmacologic or genetic manipulations in heart failure.