Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice
Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice
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DOI：
10.1073/pnas.96.11.6400
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发表时间：
1999-05-25
影响因子：
11.1
通讯作者：
Liggett, SB
中科院分区：
文献类型：
--
作者：
Dorn, GW;Tepe, NM;Liggett, SB
G α q在心脏中的转基因过表达引发了导致偏心肥厚表型、心室功能下降、肥厚相关基因的显著表达和β -肾上腺素能受体（β AR）功能下降的事件。β - AR功能障碍在这种失败表型发展中的作用是通过β - AR激酶（β ARK）的转基因共表达来描述的，β - AR激酶（β ARK）的作用是抑制激酶，或伴随β (2)AR的过表达，低(约30倍，G α q/ β (2)AR(L))，中等(约140倍，G α q/ β (2)AR(M))和高(约1000倍，G α q/ β (2)AR(H))水平高于背景β AR密度。β - ARK抑制剂的表达对表型没有影响，这与G α q小鼠中缺乏增加的β - ARK水平一致。与此形成鲜明对比的是，G α q/ β (2)AR(L)小鼠表现出肥厚和静息心室功能的恢复，心房利钠因子和α -骨骼肌动蛋白mRNA的表达降低。尽管不能排除β (2)AR/AC信号区隔化的恢复，但这些效应发生在心肌粗膜中基础或激动剂刺激的腺苷酸环化酶（AC）活性没有任何改善的情况下。G α q/ β (2)AR(M)小鼠中受体的高表达导致AC活性的恢复，但肥厚、心室功能和胎儿基因的表达不受影响或恶化。G α q/ β (2)AR(H)小鼠的过表达量约为1000倍，大多数小鼠在5周时因心脏肥大而死亡。因此，尽管过度、不受控制或广泛增强X AR信号在心力衰竭中似乎是有害的，但通过过度表达β (2)AR亚型到有限水平的选择性增强不仅可以恢复心室功能，还可以逆转心脏肥厚。
Transgenic overexpression of G alpha q in the heart triggers events leading to a phenotype of eccentric hypertrophy, depressed ventricular function, marked expression of hypertrophy-associated genes, and depressed beta-adrenergic receptor (beta AR) function. The role of beta AR dysfunction in the development of this failure phenotype was delineated by transgenic coexpression of the carboxyl terminus of the beta AR kinase (beta ARK), which acts to inhibit the kinase, or concomitant overexpression of the beta(2)AR at low (approximate to 30-fold, G alpha q/beta(2)AR(L)), moderate (approximate to 140-fold, G alpha q/beta(2)AR(M)), and high (approximate to 1,000-fold, G alpha q/beta(2)AR(H)) levels above background beta AR density. Expression of the beta ARK inhibitor had no effect on the phenotype, consistent with the lack of increased beta ARK levels in G alpha q mice. In marked contrast, G alpha q/beta(2)AR(L) mice displayed rescue of hypertrophy and resting ventricular function and decreased cardiac expression of atrial natriuretic factor and alpha-skeletal actin mRNA. These effects occurred in the absence of any improvement in basal or agonist-stimulated adenylyl cyclase (AC) activities in crude cardiac membranes, although restoration of a compartmentalized beta(2)AR/AC signal cannot be excluded. Higher expression of receptors in G alpha q/beta(2)AR(M) mice resulted in salvage of AC activity, but hypertrophy, ventricular function, and expression of fetal genes were unaffected or worsened. With approximate to 1,000-fold overexpression, the majority of G alpha q/beta(2)AR(H) mice died with cardiomegaly at 5 weeks. Thus, although it appears that excessive, uncontrolled, or generalized augmentation of X AR signaling is deleterious in heart failure, selective enhancement by overexpressing the beta(2)AR subtype to limited levels restores not only ventricular function but also reverses cardiac hypertrophy.