PMID- 12883532
OWN - NLM
STAT- MEDLINE
DCOM- 20030917
LR  - 20131121
IS  - 0969-7128 (Print)
IS  - 0969-7128 (Linking)
VI  - 10
IP  - 16
DP  - 2003 Aug
TI  - Effects of two Gbetagamma-binding proteins--N-terminally truncated phosducin and 
      beta-adrenergic receptor kinase C terminus (betaARKct)--in heart failure.
PG  - 1354-61
AB  - Myocardial overexpression of the C-terminus of beta-adrenergic receptor kinase 
      (betaARKct) has been shown to result in a positive inotropic effect or an 
      improvement of survival in heart failure. However, it is not clear whether this 
      beneficial effect is mainly because of dominant-negative inhibition of betaARK1, 
      and a consecutive resensitization of beta-adrenergic receptors (betaAR), or 
      rather due to inhibition of other Gbetagamma-mediated effects. In this study, we 
      tested whether overexpression of N-terminally truncated phosducin 
      (nt-del-phosducin), another Gbetagamma-binding protein that does not resensitize 
      betaARs owing to simultaneous inhibition of GDP release from Galpha subunits, 
      shows the same effects as betaARKct. Adenoviral gene transfer was used to express 
      nt-del-phosducin and betaARKct in isolated ventricular cardiomyocytes and in 
      myocardium of rabbits, which suffered from heart failure because of rapid 
      ventricular pacing. BetaAR-stimulated cAMP formation was increased by betaARKct, 
      but not by nt-del-phosducin, whereas both proteins inhibited Gbetagamma-mediated 
      effects. Both transgenes also increased contractility of normal and failing 
      isolated cardiomyocytes and improved contractility in rabbits with heart failure 
      after gene transfer in vivo. In conclusion, overexpression of nt-del-phosducin 
      enhances the contractility of cardiomyocytes to the same extent as betaARKct, 
      suggesting that the effects of betaARKct might be owing to inhibition of 
      Gbetagamma rather than to betaAR resensitization.
FAU - Li, Z
AU  - Li Z
AD  - ProCorde, Martinsried, Germany.
FAU - Laugwitz, K-L
AU  - Laugwitz KL
FAU - Pinkernell, K
AU  - Pinkernell K
FAU - Pragst, I
AU  - Pragst I
FAU - Baumgartner, C
AU  - Baumgartner C
FAU - Hoffmann, E
AU  - Hoffmann E
FAU - Rosport, K
AU  - Rosport K
FAU - Munch, G
AU  - Munch G
FAU - Moretti, A
AU  - Moretti A
FAU - Humrich, J
AU  - Humrich J
FAU - Lohse, M J
AU  - Lohse MJ
FAU - Ungerer, M
AU  - Ungerer M
LA  - eng
PT  - Journal Article
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (Eye Proteins)
RN  - 0 (GTP-Binding Protein Regulators)
RN  - 0 (Phosphoproteins)
RN  - 0 (phosducin)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.15 (beta-Adrenergic Receptor Kinases)
RN  - EC 3.1.4.- (Type C Phospholipases)
RN  - EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Cardiac Pacing, Artificial
MH  - Cyclic AMP/metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/*genetics
MH  - Eye Proteins/*genetics
MH  - GTP-Binding Protein Regulators
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/administration & dosage
MH  - Heart Failure/*therapy
MH  - Heterotrimeric GTP-Binding Proteins/metabolism
MH  - Humans
MH  - Models, Animal
MH  - Myocardial Contraction
MH  - Myocardium/*metabolism
MH  - Myocytes, Cardiac/metabolism
MH  - Phosphoproteins/*genetics
MH  - Rabbits
MH  - Type C Phospholipases/metabolism
MH  - beta-Adrenergic Receptor Kinases
EDAT- 2003/07/29 05:00
MHDA- 2003/09/18 05:00
CRDT- 2003/07/29 05:00
PHST- 2003/07/29 05:00 [pubmed]
PHST- 2003/09/18 05:00 [medline]
PHST- 2003/07/29 05:00 [entrez]
AID - 3301995 [pii]
AID - 10.1038/sj.gt.3301995 [doi]
PST - ppublish
SO  - Gene Ther. 2003 Aug;10(16):1354-61. doi: 10.1038/sj.gt.3301995.