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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/H1299    most recent 00017.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Sucharov, C. C. Articles by Bristow, M. R. Search for Related Content PubMed PubMed Citation Articles by Sucharov, C. C. Articles by Bristow, M. R.

A ₁-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction

University of Colorado Cardiovascular Institute, Denver, Aurora and Boulder, Colorado

Submitted 4 January 2006 ; accepted in final form 24 February 2006

-Adrenergic signaling plays an important role in the natural history of dilated cardiomyopathies. Chronic activation of -adrenergic receptors (₁-AR and ₂-AR) during periods of cardiac stress ultimately harms the failing heart by mechanisms that include alterations in gene expression. Here, we show that stimulation of -ARs with isoproterenol in neonate rat ventricular myocytes causes a "fetal" response in the relative activities of the human cardiac fetal and/or adult gene promoters that includes repression of the human and rat -myosin heavy chain (-MyHC) promoters with simultaneous activation of the human atrial natriuretic peptide (ANP) and rat -MyHC promoters. We also show that the promoter changes correlate with changes in endogenous gene expression as measured by mRNA expression. Furthermore, we show that these changes are specifically mediated by the ₁-AR, but not the ₂-AR, and are independent of ₁-AR stimulation. We also demonstrate that the fetal gene response is independent of cAMP and protein kinase A, whereas inhibition of Ca²⁺/calmodulin-dependent protein kinase (CaMK) pathway blocks isoproterenol-mediated fetal gene program induction. Finally, we show that induction of the fetal program is dependent on activation of the L-type Ca²⁺ channel. We conclude that in neonatal rat cardiac myocytes, agonist-occupied ₁-AR mobilizes Ca²⁺ stores to activate fetal gene induction through cAMP independent pathways that involve CaMK.

myosin; adenosine 3',5'-cyclic monophosphate

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