title: G-protein-coupled receptor kinase 2-mediated desensitization of adiponectin receptor 1 in failing heart.
abstract: BACKGROUND
  Phosphorylative desensitization of G-protein-coupled receptors contributes significantly to post-myocardial infarction (MI) remodeling and heart failure (HF). Here, we determined whether adiponectin receptors (AdipoRs) 1 and 2 (the 7-transmembrane domain-containing receptors mediating adiponectin functions) are phosphorylatively modified and functionally impaired after MI.
  
  
  RESULTS
  Post-MI HF was induced by coronary artery occlusion. Receptor phosphorylation, kinase expression, and adiponectin function were determined via in vivo, ex vivo, and in vitro models. AdipoR1 and AdipoR2 are not phosphorylated in the normal heart. However, AdipoR1 was significantly phosphorylated after MI, peaking at 7 days and remaining significantly phosphorylated thereafter. The extent of post-MI AdipoR1 phosphorylation positively correlated with the expression level of GPCR kinase (GRK) 2, the predominant GRK isoform upregulated in the failing heart. Cardiac-specific GRK2 knockout virtually abolished post-MI AdipoR1 phosphorylation, whereas virus-mediated GRK2 overexpression significantly phosphorylated AdipoR1 and blocked adiponectin metabolic-regulatory/anti-inflammatory signaling. Mass spectrometry identified serine-7, threonine-24, and threonine-53 (residues located in the n-terminal intracellular AdipoR1 region) as the GRK2 phosphorylation sites. Ex vivo experiments demonstrated that adenosine monophosphate-activated protein kinase activation and the anti-tumor necrosis factor-α effect of adiponectin were significantly inhibited in cardiomyocytes isolated from nonischemic area 7 days after MI. In vivo experiments demonstrated that acute adiponectin administration-induced cardiac GLUT4 translocation and endothelial nitric oxide synthase phosphorylation were blunted 7 days after MI. Continuous adiponectin administration beginning 7 days after MI failed to protect the heart from adverse remodeling and HF progression. Finally, cardiac-specific GRK2 knockdown restored the cardioprotective effect of adiponectin.
  
  
  CONCLUSIONS
  AdipoR1 is phosphorylatively modified and desensitized by GRK2 in failing cardiomyocytes, contributing to post-MI remodeling and HF progression.
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.). xin.ma@jefferson.edu yajing.wang@jefferson.edu.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Gaizheng
authors.initials: G
authors.lastname: Liu
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Li
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: From Department of Emergency Medicine (Y.W., W.B.L., Y.W., G.L., J.-J.L., X.W., Y.Y., X.-L.M.) and Center for Translational Medicine, Department of Medicine (X.-L.M.), Thomas Jefferson University, Philadelphia, PA; and Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.J.K.). xin.ma@jefferson.edu yajing.wang@jefferson.edu.
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D054419:Receptors, Adiponectin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: C475418:ADIPOR1 protein, human; D052242:Adiponectin; D051275:Glucose Transporter Type 4; D054419:Receptors, Adiponectin; D011993:Recombinant Fusion Proteins; C495693:Slc2a4 protein, mouse; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D055372:AMP-Activated Protein Kinases
keywords: adipokines; heart failure; phosphorylation; receptors, adiponectin