Regulation of myocardial betaARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing alpha1B-adrenergic receptors.
OBJECTIVE
Using a transgenic mouse model of myocardial-targeted overexpression of the wild-type alpha1B adrenergic receptor (AR) (Tg alpha43), we studied the role of the betaAR kinase (betaARK1) in the evolution of myocardial hypertrophy and its transition to heart failure (HF).


BACKGROUND
Increased myocardial expression of betaARK1 has been shown to be associated with HF and certain models of hypertrophy.


METHODS
Tg alpha43 mice and their nontransgenic littermate controls were treated with the alpha1AR 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 betaARK1 expression. However, Tg alpha43 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 alpha43 mice resulted in an exaggerated hypertrophic response accompanied by significant cardiac biochemical abnormalities that are normally associated with HF, including fetal gene expression, reduced betaAR density and enhanced betaARK1 expression. We also found reduced myocardial stores of the sympathetic neurotransmitter neuropeptide Y.


CONCLUSIONS
These data suggest that PE-treated Tg alpha43 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 alpha1B AR signaling and suggest that betaARK1 is a key molecule in the transition of myocardial hypertrophy to HF.
Iaccarino
G
G
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Keys
J R
JR
Rapacciuolo
A
A
Shotwell
K F
KF
Lefkowitz
R J
RJ
Rockman
H A
HA
Koch
W J
WJ
D000316:Adrenergic alpha-Agonists; D000818:Animals; D001835:Body Weight; D006332:Cardiomegaly / Q000139:chemically induced / Q000150:complications / Q000201:enzymology*; D002311:Cardiomyopathy, Dilated / Q000209:etiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009478:Neuropeptide Y / Q000378:metabolism; D009929:Organ Size; D010656:Phenylephrine; D012333:RNA, Messenger / Q000096:biosynthesis; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics* / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction; D051552:beta-Adrenergic Receptor Kinases
C547714:Adra1a protein, mouse; C547717:Adra1b protein, mouse; D000316:Adrenergic alpha-Agonists; D009124:Muscle Proteins; D009478:Neuropeptide Y; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases