Transient cardiac expression of constitutively active Gαq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways
Transient cardiac expression of constitutively active Gαq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways
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DOI：
10.1073/pnas.95.23.13893
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发表时间：
1998-11-10
影响因子：
11.1
通讯作者：
Neer, EJ
中科院分区：
文献类型：
--
作者：
Mende, U;Kagen, A;Neer, EJ
心脏肥大和扩张可由异源三聚体G蛋白介导的信号转导途径的刺激引起，特别是G（q），其α亚基激活磷脂酶C β我们现在报道了一种血凝素（HA）表位标记的，G（q）α亚基组成型活性突变体在转基因小鼠心脏中的HA α（q）* 足以诱导心脏肥大和扩张，其在起始刺激变得不可检测后继续进展。在2周时，HA α（q）* 蛋白的表达低于内源性α（q/11）的50%，并且转基因心脏在形态上基本正常。尽管HA α（q）* 蛋白在4周时下降，到10周时检测不到，但动物发生心脏肥大和扩张，并在8周和30周前死于心力衰竭。随着病理的发展？内源性α（q/11）升高（心房2.9倍;心室1.8倍）。在2周时，基础PLC活性在心房而不是心室中增加9至10倍。到10周时，两者都升高，可能是因为内源性α（q/11）升高。我们的结论是，由早期，短暂的HA α（q）* 表达引起的病理变化部分维持在信号转导和其他途径的代偿性变化。环孢菌素A（CsA）防止由钙调磷酸酶激活引起的肥大[Molkentin，J，D.，Lu，J，-R，，Antos，C，L.，Markham，B.，理查森，J.，Robbins，J.，格兰特，S。R & Olson，E. N.（1998）Cell 93，215-228]。由于HA α（q）* 作用于钙调磷酸酶的上游，我们假设HA α（q）* 可能启动导致肥大和扩张的其他途径。用CsA治疗HA α（q）* 小鼠减少了肥大表型的某些方面，但不是全部，这表明涉及多个途径。
Cardiac hypertrophy and dilatation can result from stimulation of signal transduction pathways mediated by heterotrimeric G proteins, especially G(q), whose alpha subunit activates phospholipase C beta (PLC beta), We now report that transient, modest expression of a hemagglutinin (HA) epitope-tagged, constitutively active mutant of the G(q)alpha subunit (HA alpha(q)*) in hearts of transgenic mice is sufficient to induce cardiac hypertrophy and dilatation that continue to progress after the initiating stimulus becomes undetectable. At 2 weeks, HA alpha(q)* protein is expressed at less than 50% of endogenous alpha(q/11), and the transgenic hearts are essentially normal morphologically. Although HA alpha(q)* protein declines at 4 weeks and is undetectable by 10 weeks, the animals develop cardiac hypertrophy and dilatation and die bem een 8 and 30 weeks in heart failure. As the pathology develops? endogenous alpha(q/11) rises (2.9-fold in atria; 1.8-fold in, ventricles). At 2 weeks, basal PLC activity is increased 9- to 10-fold in atria but not ventricles. By 10 weeks, it is elevated in both, presumably because of the rise in endogenous alpha(q/11). We conclude that the pathological changes initiated by early, transient HA alpha(q)* expression are maintained in part by compensatory changes in signal transduction and other pathways. Cyclosporin A (CsA) prevents hypertrophy caused by activation of calcineurin [Molkentin, J, D., Lu, J,-R,, Antos, C, L., Markham, B., Richardson, J., Robbins, J., Grant, S. R & Olson, E. N. (1998) Cell 93, 215-228]. Because HA alpha(q)* acts upstream of calcineurin, we hypothesized that HA alpha(q)* might initiate additional pathways leading to hypertrophy and dilatation. Treating HA alpha(q)* mice with CsA diminished some, but not all, aspects of the hypertrophic phenotype, suggesting that multiple pathways are involved.