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

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Abstract

OBJECTIVES

Using a transgenic mouse model of myocardial-targeted overexpression of the wild-type α1Badrenergic receptor (AR) (Tgα43), we studied the role of the βAR kinase (βARK1) in the evolution of myocardial hypertrophy and its transition to heart failure (HF).

BACKGROUND

Increased myocardial expression of βARK1 has been shown to be associated with HF and certain models of hypertrophy.

METHODS

Tgα43 mice and their nontransgenic littermate controls were treated with the α1AR 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 βARK1 expression. However, Tgα43 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 Tgα43 mice resulted in an exaggerated hypertrophic response accompanied by significant cardiac biochemical abnormalities that are normally associated with HF, including fetal gene expression, reduced βAR density and enhanced βARK1 expression. We also found reduced myocardial stores of the sympathetic neurotransmitter neuropeptide Y.

CONCLUSIONS

These data suggest that PE-treated Tgα43 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 α1BAR signaling and suggest that βARK1 is a key molecule in the transition of myocardial hypertrophy to HF.

Abbreviations

ANF
atrial natriuretic factor
AR
adrenergic receptor
βARK1
βAR 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
Tgα43
transgenic mice with cardiac targeted overexpression of the wild-type α1B-AR

Cited by (0)

This work was supported in part by the National Institutes of Health grants HL-16037 (R.J.L.), HL-61690 (W.J.K.) and fellowships from the North Carolina Affiliate of the American Heart Association (G.I.) and Telethon Fondazione Onlus (G.I.). Robert J. Lefkowitz is an investigator at the Howard Hughes Medical Institute.