RGD Reference Report - Transient cardiac expression of constitutively active Galphaq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways.

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Transient cardiac expression of constitutively active Galphaq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways.
Authors:	Mende, U Kagen, A Cohen, A Aramburu, J Schoen, FJ Neer, EJ
Citation:	Mende U, etal., Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13893-8.
RGD ID:	1598475
Pubmed:	PMID:9811897 (View Abstract at PubMed)
PMCID:	PMC24952 (View Article at PubMed Central)
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 (HAalphaq) 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, HAalphaq protein is expressed at less than 50% of endogenous alphaq/11, and the transgenic hearts are essentially normal morphologically. Although HAalphaq 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 HAalphaq 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 HAalphaq acts upstream of calcineurin, we hypothesized that HAalphaq 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.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
GNAQ	Human	Cardiomegaly		ISO	Gnaq (Mus musculus)		RGD
Gnaq	Rat	Cardiomegaly		ISO	Gnaq (Mus musculus)		RGD
Gnaq	Mouse	Cardiomegaly		IDA			RGD
GNAQ	Human	dilated cardiomyopathy		ISO	Gnaq (Mus musculus)		RGD
Gnaq	Rat	dilated cardiomyopathy		ISO	Gnaq (Mus musculus)		RGD
Gnaq	Mouse	dilated cardiomyopathy		IDA			RGD

Objects Annotated

Genes (Rattus norvegicus)

Gnaq (G protein subunit alpha q)

Genes (Mus musculus)

Gnaq (guanine nucleotide binding protein, alpha q polypeptide)

Genes (Homo sapiens)

GNAQ (G protein subunit alpha q)

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