First Author | Mende U | Year | 1998 |
Journal | Proc Natl Acad Sci U S A | Volume | 95 |
Issue | 23 | Pages | 13893-8 |
PubMed ID | 9811897 | Mgi Jnum | J:204274 |
Mgi Id | MGI:5529911 | Doi | 10.1073/pnas.95.23.13893 |
Citation | Mende U, et al. (1998) Transient cardiac expression of constitutively active Galphaq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. Proc Natl Acad Sci U S A 95(23):13893-8 |
abstractText | Cardiac hypertrophy and dilatation can result from stimulation of signal transduction pathways mediated by heterotrimeric G proteins, especially Gq, whose alpha subunit activates phospholipase Cbeta (PLCbeta). We now report that transient, modest expression of a hemagglutinin (HA) epitope-tagged, constitutively active mutant of the Gq alpha subunit (HAalpha*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, HAalpha*q protein is expressed at less than 50% of endogenous alphaq/11, and the transgenic hearts are essentially normal morphologically. Although HAalpha*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 alphaq/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 alphaq/11. We conclude that the pathological changes initiated by early, transient HAalpha*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 HAalpha*q acts upstream of calcineurin, we hypothesized that HAalpha*q might initiate additional pathways leading to hypertrophy and dilatation. Treating HAalpha*q mice with CsA diminished some, but not all, aspects of the hypertrophic phenotype, suggesting that multiple pathways are involved. |