Gene-mediated inhibition of the b-adrenergic receptor kinase: a new therapeutic strategy for heart failure.
Molecular changes that take place during the evolution of heart failure (HF), especially the well characterized beta-adrenergic receptor (betaAR) signaling abnormalities, represent attractive targets for myocardial gene therapy. The beta-adrenergic receptor kinase (betaARK1 or GRK2) is a cytosolic enzyme that phosphorylates only agonist-occupied betaARs as well as other G protein-coupled receptors (GPCRs), leading to desensitization and functional uncoupling. betaARK1 levels and activity are elevated in the failing heart and therefore, it has recently been evaluated as a potential target for novel HF treatment. This review summarizes recent results obtained in transgenic mouse models as well as in animals where a betaARK1 inhibitor peptide (betaARKct) was delivered via the coronary arteries by exogenous gene transfer. These results strongly suggest that betaARK1 inhibition may represent a significant improvement in HF therapy.
Tevaearai
H T
HT
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
Eckhart
A D
AD
Koch
W J
WJ
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D003331:Coronary Vessels; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006333:Heart Failure / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides; D011994:Recombinant Proteins
D002352:Carrier Proteins; D010455:Peptides; D011994:Recombinant Proteins; C445259:beta-adrenergic receptor kinase inhibitory peptide