Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

J Biol Chem. 2016 Feb 5;291(6):2583-600. doi: 10.1074/jbc.M115.702688. Epub 2015 Dec 15.


Impairment of myocardial fatty acid substrate metabolism is characteristic of late-stage heart failure and has limited treatment options. Here, we investigated whether inhibition of G-protein-coupled receptor kinase 2 (GRK2) could counteract the disturbed substrate metabolism of late-stage heart failure. The heart failure-like substrate metabolism was reproduced in a novel transgenic model of myocardium-specific expression of fatty acid synthase (FASN), the major palmitate-synthesizing enzyme. The increased fatty acid utilization of FASN transgenic neonatal cardiomyocytes rapidly switched to a heart failure phenotype in an adult-like lipogenic milieu. Similarly, adult FASN transgenic mice developed signs of heart failure. The development of disturbed substrate utilization of FASN transgenic cardiomyocytes and signs of heart failure were retarded by the transgenic expression of GRKInh, a peptide inhibitor of GRK2. Cardioprotective GRK2 inhibition required an intact ERK axis, which blunted the induction of cardiotoxic transcripts, in part by enhanced serine 273 phosphorylation of Pparg (peroxisome proliferator-activated receptor γ). Conversely, the dual-specific GRK2 and ERK cascade inhibitor, RKIP (Raf kinase inhibitor protein), triggered dysfunctional cardiomyocyte energetics and the expression of heart failure-promoting Pparg-regulated genes. Thus, GRK2 inhibition is a novel approach that targets the dysfunctional substrate metabolism of the failing heart.

Keywords: GRK2; cardiac metabolism; extracellular signal-regulated kinase (ERK); fatty acid synthase (FAS); heart failure; microarray; peroxisome proliferator-activated receptor; transgenic mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fatty Acid Synthase, Type I / genetics
  • Fatty Acid Synthase, Type I / metabolism*
  • G-Protein-Coupled Receptor Kinase 2 / genetics
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • Heart Failure / enzymology*
  • Heart Failure / genetics
  • Heart Failure / pathology
  • Mice
  • Mice, Transgenic
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phosphatidylethanolamine Binding Protein / genetics
  • Phosphatidylethanolamine Binding Protein / metabolism


  • PPAR gamma
  • Phosphatidylethanolamine Binding Protein
  • Raf kinase inhibitory protein, mouse
  • Fatty Acid Synthase, Type I
  • GRK2 protein, mouse
  • G-Protein-Coupled Receptor Kinase 2