A β1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction

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 and/or adult gene promoters that includes repression of the human and rat alpha-myosin heavy chain (alpha-MyHC) promoters with simultaneous activation of the human atrial natriuretic peptide (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)-AR stimulation. We also demonstrate that the fetal gene response is independent of cAMP and protein kinase A, whereas inhibition of Ca(2+)/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 Ca(2+) channel. We conclude that in neonatal rat cardiac myocytes, agonist-occupied beta(1)-AR mobilizes Ca(2+) stores to activate fetal gene induction through cAMP independent pathways that involve CaMK.