Common genomic response in different mouse models of beta-adrenergic-induced cardiomyopathy.
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.


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.
Gaussin
Vinciane
V
University of Medicine and Dentistry of New Jersey and New Jersey Medical School, Newark, NJ 07101, USA.
Tomlinson
James E
JE
Depre
Christophe
C
Engelhardt
Stefan
S
Antos
Christopher L
CL
Takagi
Gen
G
Hein
Lutz
L
Topper
James N
JN
Liggett
Stephen B
SB
Olson
Eric N
EN
Lohse
Martin J
MJ
Vatner
Stephen F
SF
Vatner
Dorothy E
DE
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D004837:Epinephrine / Q000502:physiology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000235:genetics / Q000517:prevention & control*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D007473:Ion Channels; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D023421:Models, Animal; D011943:Receptors, Adrenergic, beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071246:Uncoupling Protein 2
D000319:Adrenergic beta-Antagonists; D018398:Homeodomain Proteins; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011943:Receptors, Adrenergic, beta; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs; D004837:Epinephrine