Mechanism of β-Adrenergic Receptor Desensitization in Cardiac Hypertrophy Is Increased β-Adrenergic Receptor Kinase*

Pressure overload cardiac hypertrophy in the mouse was achieved following 7 days of transverse aortic constriction. This was associated with marked β-adrenergic receptor (β-AR) desensitization in vivo, as determined by a blunted inotropic response to dobutamine. Extracts from hypertrophied hearts had ≈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 β-adrenergic receptor kinase (βARK). Although overexpression of a βARK inhibitor in hearts of transgenic mice did not alter the development of cardiac hypertrophy, the β-AR desensitization associated with pressure overload hypertrophy was prevented. To determine whether the induction of βARK occurred because of a generalized response to cellular hypertrophy, βARK activity was measured in transgenic mice homozygous for oncogenic ras overexpression in the heart. Despite marked cardiac hypertrophy, no difference in βARK activity was found in these mice overexpressing oncogenic ras compared with controls. Taken together, these data suggest that βARK is a central molecule involved in alterations of β-AR signaling in pressure overload hypertrophy. The mechanism for the increase in βARK activity appears not to be related to the induction of cellular hypertrophy but to possibly be related to neurohumoral activation.

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