Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level.
Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level.
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DOI：
10.1161/01.cir.101.14.1707
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发表时间：
2000-04
期刊：
影响因子：
37.8
通讯作者：
Stephen B. Liggett;N. M. Tepe;John N. Lorenz;Amy M. Canning;Tamara D. Jantz;S. Mitarai;Atsuko Yatani;Gerald W. Dorn
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文献类型：
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作者：
Stephen B. Liggett;N. M. Tepe;John N. Lorenz;Amy M. Canning;Tamara D. Jantz;S. Mitarai;Atsuko Yatani;Gerald W. Dorn
转基因心脏β（2）-肾上腺素能受体（AR）过表达导致小鼠信号传导和心脏功能增强，而相对低水平的转基因表达的G（α）或β（1）AR导致心室衰竭的表型。尚未报道β AR过表达水平与生化、分子和生理后果之间的潜在关系。方法和结果我们建立了心脏表达β 2 AR的转基因小鼠，表达量分别为3690、7120、9670和23300 fmol/mg，分别是背景β AR表达量的60、100、150和350倍。所有的线表现出增强的基础腺苷酸环化酶的激活，但减少毛喉素和氟化钠刺激的腺苷酸环化酶的活动。最高表达系的小鼠发展为快速进行性纤维化扩张型心肌病，并在25+/-1周龄时死于心力衰竭。60倍线表现出增强的基础心脏功能，而死亡率增加1年后，而100倍的过度表达发展成纤维化心肌病和心力衰竭，死亡发生在41+/-1周龄。腺苷酸环化酶激活与早期或延迟失代偿无关。除了350倍过表达者外，普萘洛尔给药使所有β 2 AR转基因动物的基线+dP/dt（max）降低至非转基因水平，表明在该表达水平下存在β 2 AR的自发激活。结论这些数据表明，心脏耐受通过60倍β（2）AR过表达而增强的收缩功能，而不损害>/=1年的时间，并且更高水平的表达导致侵袭性或迟发性心肌病。心脏中增强β AR功能的后果似乎高度依赖于哪些信号元件增加以及增加到何种程度。
BACKGROUND Transgenic cardiac beta(2)-adrenergic receptor (AR) overexpression has resulted in enhanced signaling and cardiac function in mice, whereas relatively low levels of transgenically expressed G(alphas) or beta(1)AR have resulted in phenotypes of ventricular failure. Potential relationships between the levels of betaAR overexpression and biochemical, molecular, and physiological consequences have not been reported. METHODS AND RESULTS We generated transgenic mice expressing beta(2)AR at 3690, 7120, 9670, and 23 300 fmol/mg in the heart, representing 60, 100, 150, and 350 times background betaAR expression. All lines showed enhanced basal adenylyl cyclase activation but a decrease in forskolin- and NaF-stimulated adenylyl cyclase activities. Mice of the highest-expressing line developed a rapidly progressive fibrotic dilated cardiomyopathy and died of heart failure at 25+/-1 weeks of age. The 60-fold line exhibited enhanced basal cardiac function without increased mortality when followed for 1 year, whereas 100-fold overexpressors developed a fibrotic cardiomyopathy and heart failure, with death occurring at 41+/-1 weeks of age. Adenylyl cyclase activation did not correlate with early or delayed decompensation. Propranolol administration reduced baseline +dP/dt(max) to nontransgenic levels in all beta(2)AR transgenics except the 350-fold overexpressors, indicating that spontaneous activation of beta(2)AR was present at this level of expression. CONCLUSIONS These data demonstrate that the heart tolerates enhanced contractile function via 60-fold beta(2)AR overexpression without detriment for a period of >/=1 year and that higher levels of expression result in either aggressive or delayed cardiomyopathy. The consequences for enhanced betaAR function in the heart appear to be highly dependent on which signaling elements are increased and to what extent.