Regulation of myocardial βARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing α1B-adrenergic receptors

OBJECTIVES Using a transgenic mouse model of myocardial-targeted overexpression of the mild-type am adrenergic receptor (AR) (Tg alpha 43), we studied the rule of the beta AR kinase (beta ARK1) in the evolution of myocardial hypertrophy and its transition to heart failure (HF). BACKGROUND Increased myocardial expression of beta ARK1 has been shown to be associated with HF and certain models of hypertrophy. METHODS Tg alpha 43 mice and their nontransgenic littermate controls were treated with the alpha (1)AR agonist phenylephrine (PE) for 3, 7 or 14 days to characterize the cardiac consequences. RESULTS Nontransgenic littermate control mice treated for 14 days with PE display cardiac hypertrophy with no increase in beta ARK1 expression. However, Tg alpha 43 animals show a reduced tolerance to 14-day PE treatment, demonstrated by reduced survival and severe cardiac hypertrophy. Moreover, PE treatment for three and seven days in Tg alpha 43 mice resulted in an exaggerated hypertrophic response accompanied by significant cardiac biochemical abnormalities that are normally associated with HF, including fetal gene expression, reduced beta AR density and enhanced beta ARK1 expression. We also found reduced myocardial stores of the sympathetic neurotransmitter neuropeptide Y. CONCLUSIONS These data suggest that PE-treated Tg alpha 43 mice have chronic activation of the cardiac sympathetic nervous system which may be responsible for the appearance of apparent maladaptive hypertrophy with an evolution towards HF and sudden death. Thus, the cardiac phenotypes found in these mice are not the direct result of enhanced alpha (1B)AR signaling and suggest that beta ARK1 is a key molecule in the transition of myocardial hypertrophy to HF. (J Am Coll Cardiol 2001;38:534-40) (C) 2001 by the American College of Cardiology.