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

TLDR

The study aimed to test whether βARK induction is a general hypertrophic response by measuring its activity in oncogenic ras transgenic hearts. Pressure‑overload hypertrophy was induced by 7‑day transverse aortic constriction, GRK activity was quantified, monoclonal antibodies identified βARK as the predominant kinase, and βARK activity was also measured in ras‑overexpressing hearts. Hypertrophic hearts displayed β‑adrenergic receptor desensitization and a ~3‑fold rise in βARK activity; βARK inhibition prevented desensitization but not hypertrophy, and ras‑induced hypertrophy showed no βARK increase, suggesting neurohumoral rather than hypertrophic regulation.

Abstract

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 <i>in vivo</i>, 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 <i>ras</i> overexpression in the heart. Despite marked cardiac hypertrophy, no difference in βARK activity was found in these mice overexpressing oncogenic <i>ras</i> 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.