Abstract
BACKGROUND: Although beta-adrenergic receptor (AR) blockade therapy
is beneficial in the treatment of heart failure, little is known
regarding the transcriptional mechanisms underlying this salutary
action. METHODS AND RESULTS: In the present study, we screened mice
overexpressing Gsalpha, beta1AR, beta2AR, or protein kinase A to
test if a common genomic pathway exists in different models with
enhanced beta-adrenergic signaling. In mice overexpressing Gsalpha,
differentially expressed genes were identified by mRNA profiling.
In addition to well-known markers of cardiac hypertrophy (atrial
natriuretic factor, CARP, and beta-myosin heavy chain), uncoupling
protein 2 (UCP2), a protein involved in the control of mitochondrial
membrane potential, and four-and-a-half LIM domain protein-1 (FHL1),
a member of the LIM protein family, were predicted to be upregulated.
Upregulation of these genes was confirmed by quantitative reverse
transcriptase-polymerase chain reaction at all time points tested
during the development of cardiomyopathy in mice overexpressing Gsalpha.
In mice overexpressing beta1AR, beta2AR, or protein kinase A, increased
UCP2 and FHL1 expression was also observed at the onset of cardiomyopathy.
BetaAR blockade treatment reversed the cardiomyopathy and suppressed
the increased expression of UCP2 and FHL1 in mice overexpressing
Gsalpha. CONCLUSIONS: UCP2 and FHL1 are important candidate genes
that correlate with the development of betaAR-induced cardiomyopathy
in different mouse models with enhanced betaAR signaling. In addition
to preserving cardiac function, betaAR blockade treatment also prevents
the genomic regulation that correlates with the onset of heart failure.
Users
Please
log in to take part in the discussion (add own reviews or comments).