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EXPERIMENTAL STUDY

Regulation of myocardial ßARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing _1B-adrenergic receptors

Guido Iaccarino, MD^* , Janelle R. Keys, PhD, Antonio Rapacciuolo, MD^*, Kyle F. Shotwell, BS, Robert J. Lefkowitz, MD^* , Howard A. Rockman, MD^* and Walter J. Koch, PhD

^* Medicine, Duke University Medical Center, Durham, North Carolina, USA
Surgery, Duke University Medical Center, Durham, North Carolina, USA
Biochemistry, Duke University Medical Center, Durham, North Carolina, USA
Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina, USA

Manuscript received November 17, 2000; revised manuscript received March 15, 2001, accepted April 24, 2001.

Reprint requests and correspondence: Dr. Walter J. Koch, Laboratory of Molecular Cardiovascular Biology, Duke University Medical Center, Room 472, MSRB, Research Drive, Durham, North Carolina 27710
koch0002{at}mc.duke.edu

OBJECTIVES

Using a transgenic mouse model of myocardial-targeted overexpression of the wild-type _1B adrenergic receptor (AR) (Tg43), we studied the role of the ßAR kinase (ßARK1) in the evolution of myocardial hypertrophy and its transition to heart failure (HF).

BACKGROUND

Increased myocardial expression of ßARK1 has been shown to be associated with HF and certain models of hypertrophy.

METHODS

Tg43 mice and their nontransgenic littermate controls were treated with the ₁AR 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 ßARK1 expression. However, Tg43 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 Tg43 mice resulted in an exaggerated hypertrophic response accompanied by significant cardiac biochemical abnormalities that are normally associated with HF, including fetal gene expression, reduced ßAR density and enhanced ßARK1 expression. We also found reduced myocardial stores of the sympathetic neurotransmitter neuropeptide Y.

CONCLUSIONS

These data suggest that PE-treated Tg43 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 _1BAR signaling and suggest that ßARK1 is a key molecule in the transition of myocardial hypertrophy to HF.

Abbreviations and Acronyms   ANF = atrial natriuretic factor   AR = adrenergic receptor   ßARK1 = ßAR kinase-1   CAM = constitutively activated mutant   cAMP = cyclic adenosine monophosphate   du = densitometry units   GPCR = G protein-coupled receptor   GRK = G protein-coupled receptor kinase   HF = heart failure   mRNA = messenger ribonucleic acid   NLC = nontransgenic littermate control   PE = phenylephrine   SERCA2a = sarcoplasmic reticulum Ca++-ATPase   Tg43 = transgenic mice with cardiac targeted overexpression of the wild-type 1B-AR

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