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J Am Coll Cardiol, 2001; 38:534-540
© 2001 by the American College of Cardiology Foundation
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EXPERIMENTAL STUDY

Regulation of myocardial ßARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing {alpha}1B-adrenergic receptors

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

* Medicine, Duke University Medical Center, Durham, North Carolina, USA
{dagger} Surgery, Duke University Medical Center, Durham, North Carolina, USA
{ddagger} 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 {alpha}1B adrenergic receptor (AR) (Tg{alpha}43), 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

Tg{alpha}43 mice and their nontransgenic littermate controls were treated with the {alpha}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, 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 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 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}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
  Tg{alpha}43 = transgenic mice with cardiac targeted overexpression of the wild-type {alpha}1B-AR




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