Effects of two Gbetagamma-binding proteins--N-terminally truncated
phosducin and beta-adrenergic receptor kinase C terminus (betaARKct)--in
heart failure
Gene Ther, 10 (16):
1354-61 (August 2003)Li, Z Laugwitz, K-L Pinkernell, K Pragst, I Baumgartner, C Hoffmann,
E Rosport, K Munch, G Moretti, A Humrich, J Lohse, M J Ungerer, M
England Gene therapy Gene Ther. 2003 Aug;10(16):1354-61..Abstract
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.