Cardiac hypertrophy is associated with increased β-adrenergic receptor kinase (βARK)

The β-adrenergic receptor (β-AR) is regulated by members of the G protein-coupled receptor kinase (GRK) family. GRK activity is increase in heart failure, however little is known about the role of GRKs in cardiac hypertrophy. Wild type mice were studied after development of left ventricular hypertrophy (LVH). created by 7 days of transverse aortic constriction (TAC) (LV weight/body weight 4.24±0.17 vs. 3.16±0.085 mg/g, mean±SEM. p<0.001). Hemodynamic evaluation in closed-chest anesthetized mice with LVH, revealed a significant attenuation of the dobutamine induced inotropic response (LV dP/dtmax) compared to sham controls indicating β-AR desensitization. As assessed by rhodopsin phosphorylation, extracts from TAC hearts had =3 fold increase in cytosolic (32.3±4.3 vs. 11.5±1.3, fmol/min/mg, p<0.001), and a 2.5 fold increase in membrane associated GRK activity. Western blotting after immunoprecipitation showed BARK protein levels to be 2 fold higher with LVH. No difference in β-AR density or Giα protein level was found in LVH hearts. To demonstrate that the in vivo β-AR desensitization was due to elevated BARK, LVH was induced in transgenic mice overexpressing a BARK inhibitor. Overexpression of the βARK inhibitor did not inhibit LVH, but prevented β-AR desensitization in vivo. These data suggest that BARK is the central molecule associated with altered BAR signaling in cardiac hypertrophy.

Duke Scholars

Author Howard Allan Rockman Medicine, Cardiology