Mechanism of beta-adrenergic receptor desensitization in cardiac hypertrophy is increased beta-adrenergic receptor kinase

Pressure overload cardiac hypertrophy in the mouse was achieved following 7 days of transverse aortic constriction, This was associated with marked beta-adrenergic receptor (beta-AR) desensitization in vivo, as determined by a blunted inotropic response to dobutamine. Extracts from hypertrophied hearts had approximate to 3-fold increase in cytosolic and membrane G protein-coupled receptor kinase (GRK) activity, Incubation with specific monoclonal antibodies to inhibit different GRK subtypes showed that the increase in activity could be attributed predominately to the beta-adrenergic receptor kinase (beta ARK), Although overexpression of a beta ARK inhibitor in hearts of transgenic mice did not alter the development of cardiac hypertrophy, the beta-AR desensitization associated with pressure overload hypertrophy was prevented, To determine whether the induction of beta ARK occurred because of a generalized response to cellular hypertrophy, beta ARK activity was measured in transgenic mice homozygous for oncogenic ras overexpression in the heart. Despite marked cardiac hypertrophy, no difference in beta ARK activity was found in these mice overexpressing oncogenic ras compared with controls, Taken together, these data suggest that beta ARK is a central molecule involved in alterations of beta-AR signaling in pressure overload hypertrophy, The mechanism for the increase in beta ARK activity appears not to be related to the induction of cellular hypertrophy but to possibly be related to neurohumoral activation.