title: G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia.
abstract: BACKGROUND
  Alterations in cardiac energy metabolism downstream of neurohormonal stimulation play a crucial role in the pathogenesis of heart failure. The chronic adrenergic stimulation that accompanies heart failure is a signaling abnormality that leads to the upregulation of G protein-coupled receptor kinase 2 (GRK2), which is pathological in the myocyte during disease progression in part owing to uncoupling of the β-adrenergic receptor system. In this study, we explored the possibility that enhanced GRK2 expression and activity, as seen during heart failure, can negatively affect cardiac metabolism as part of its pathogenic profile.
  
  
  RESULTS
  Positron emission tomography studies revealed in transgenic mice that cardiac-specific overexpression of GRK2 negatively affected cardiac metabolism by inhibiting glucose uptake and desensitization of insulin signaling, which increases after ischemic injury and precedes heart failure development. Mechanistically, GRK2 interacts with and directly phosphorylates insulin receptor substrate-1 in cardiomyocytes, causing insulin-dependent negative signaling feedback, including inhibition of membrane translocation of the glucose transporter GLUT4. This identifies insulin receptor substrate-1 as a novel nonreceptor target for GRK2 and represents a new pathological mechanism for this kinase in the failing heart. Importantly, inhibition of GRK2 activity prevents postischemic defects in myocardial insulin signaling and improves cardiac metabolism via normalized glucose uptake, which appears to participate in GRK2-targeted prevention of heart failure.
  
  
  CONCLUSIONS
  Our data provide novel insights into how GRK2 is pathological in the injured heart. Moreover, it appears to be a critical mechanistic link within neurohormonal crosstalk governing cardiac contractile signaling/function through β-adrenergic receptors and metabolism through the insulin receptor.
authors.affiliation: George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Ciccarelli
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rengo
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Wei
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Peroutka
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Gold
authors.forename: Anna
authors.initials: A
authors.lastname: Gumpert
authors.forename: Mai
authors.initials: M
authors.lastname: Chen
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Otis
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics* / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006333:Heart Failure / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000628:therapy; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D049268:Positron-Emission Tomography; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C495692:SLC2A4 protein, human; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2