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Transient cardiac expression of constitutively active Gα q leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways

1998; National Academy of Sciences; Volume: 95; Issue: 23 Linguagem: Inglês

10.1073/pnas.95.23.13893

1091-6490

Ulrike Mende, Alexander Kagen, Allison Cohen, J. Aramburu, Frederick J. Schoen, Eva J. Neer,

Cardiac electrophysiology and arrhythmias

Cardiac hypertrophy and dilatation can result from stimulation of signal transduction pathways mediated by heterotrimeric G proteins, especially G q , whose α subunit activates phospholipase Cβ (PLCβ). We now report that transient, modest expression of a hemagglutinin (HA) epitope-tagged, constitutively active mutant of the G q α subunit (HAα * 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, HAα * q protein is expressed at less than 50% of endogenous α q/11 , and the transgenic hearts are essentially normal morphologically. Although HAα * q protein declines at 4 weeks and is undetectable by 10 weeks, the animals develop cardiac hypertrophy and dilatation and die between 8 and 30 weeks in heart failure. As the pathology develops, endogenous α 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 α q/11 . We conclude that the pathological changes initiated by early, transient HAα * 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 HAα * q acts upstream of calcineurin, we hypothesized that HAα * q might initiate additional pathways leading to hypertrophy and dilatation. Treating HAα * q mice with CsA diminished some, but not all, aspects of the hypertrophic phenotype, suggesting that multiple pathways are involved.