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Am J Physiol Heart Circ Physiol (February 24, 2006). doi:10.1152/ajpheart.00017.2006
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Submitted on January 5, 2006
Accepted on February 22, 2006

A {beta}1-adrenergic receptor, CaM Kinase II dependent pathway mediates cardiac myocyte fetal gene induction

Carmen C Sucharov1, Peter D Mariner1, Karin R Nunley1, Carlin S Long1, Leslie A Leinwand1, and Michael R Bristow1*

1 Cardiology, University of Colorado Cardiovascular Institute, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: michael.bristow{at}uchsc.edu.

{beta}-adrenergic signaling plays an important role in the natural history of dilated cardiomyopathies. Chronic activation of {beta}-adrenergic receptors ({beta}1-AR and {beta}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 {beta}-ARs with isoproterenol in neonate rat ventricular myocytes causes a "fetal" response in the relative activities of the human cardiac fetal/adult gene promoters that includes repression of the human and rat {alpha}-MyHC promoters with simultaneous activation of the human ANP and rat {beta}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 {beta}1-AR but not the {beta}2-AR, and are independent of {alpha}1-adrenergic receptor stimulation. We also demonstrate that the fetal gene response is independent of cAMP and PKA while 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 L-Type Ca2+ channel (LTCC). We conclude that in neonatal rat cardiac myocytes, agonist occupied {beta}1-AR mobilizes Ca2+ stores to activate fetal gene induction through cAMP independent pathways that involve CaMK.




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