The increase in
protein activity and upregulation of
G-protein coupled receptor kinase 2 (GRK2) is a hallmark of cardiac stress and
heart failure. Inhibition of GRK2 improved cardiac function and survival and diminished cardiac remodeling in various animal
heart failure models. The aim of the present study was to investigate the effects of GRK2 on
cardiac hypertrophy and dissect potential molecular mechanisms. In mice we observed increased GRK2
mRNA and
protein levels following transverse aortic constriction (TAC). Conditional GRK2 knockout mice showed attenuated hypertrophic response with preserved ventricular geometry 6 weeks after TAC operation compared to wild-type animals. In isolated neonatal rat ventricular cardiac myocytes stimulation with
angiotensin II and
phenylephrine enhanced GRK2 expression leading to enhanced signaling via
protein kinase B (PKB or Akt), consecutively inhibiting
glycogen synthase kinase 3 beta (GSK3β), such promoting nuclear accumulation and activation of nuclear factor of activated T-cells (NFAT). Cardiac myocyte
hypertrophy induced by in vitro GRK2 overexpression increased the cytosolic interaction of GRK2 and
phosphoinositide 3-kinase γ (PI3Kγ). Moreover, inhibition of PI3Kγ as well as GRK2 knock down prevented Akt activation resulting in halted NFAT activity and reduced cardiac myocyte
hypertrophy. Our data show that enhanced GRK2 expression triggers
cardiac hypertrophy by GRK2-PI3Kγ mediated Akt phosphorylation and subsequent inactivation of GSK3β, resulting in enhanced NFAT activity.