title: Downregulation of G protein-coupled receptor kinase 2 levels enhances cardiac insulin sensitivity and switches on cardioprotective gene expression patterns.
abstract: G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signaling. GRK2 downregulation improves insulin sensitivity and prevents systemic insulin resistance. Cardiac GRK2 levels are increased in human heart failure, while genetically inhibiting GRK2 leads to cardioprotection in mice. However, the molecular basis underlying the deleterious effects of GRK2 up-regulation and the beneficial effects of its inhibition in the heart are not fully understood. Therefore, we have explored the interconnections among a systemic insulin resistant status, GRK2 dosage and cardiac insulin sensitivity in adult (9 month-old) animals. GRK2(+/-) mice display enhanced cardiac insulin sensitivity and mild heart hypertrophy with preserved systolic function. Cardiac gene expression is reprogrammed in these animals, with increased expression of genes related to physiological hypertrophy, while the expression of genes related to pathological hypertrophy or to diabetes/obesity co-morbidities is repressed. Notably, we find that cardiac GRK2 levels increase in situations where insulin resistance develops, such as in ob/ob mice or after high fat diet feeding. Our data suggest that GRK2 downregulation/inhibition can help maintain cardiac function in the face of co-morbidities such as insulin resistance, diabetes or obesity by sustaining insulin sensitivity and promoting a gene expression reprogramming that confers cardioprotection.
authors.affiliation: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lucas
authors.affiliation: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Jurado-Pueyo
authors.affiliation: Division of Cardiovascular Sciences, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Fortuño
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, CIBERDEM, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Veledo
authors.affiliation: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Vila-Bedmar
authors.affiliation: Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Jiménez-Borreguero
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lazcano
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University, Philadelphia, USA.
authors.forename: Ehre
authors.initials: E
authors.lastname: Gao
authors.affiliation: Metabolic Research Laboratory, Universidad de Navarra, CIBERobn, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gómez-Ambrosi
authors.affiliation: Metabolic Research Laboratory, Universidad de Navarra, CIBERobn, Pamplona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Frühbeck
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University, Philadelphia, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Division of Cardiovascular Sciences, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Cardiology and Cardiovascular Surgery, University Clinic, University of Navarra, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
authors.affiliation: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, Madrid, Spain. Electronic address: fmayor@cbm.uam.es.
authors.forename: Federico
authors.initials: F
authors.lastname: Mayor
authors.affiliation: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, Madrid, Spain. Electronic address: cmurga@cbm.uam.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Murga
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D015536:Down-Regulation; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; C495693:Slc2a4 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2
keywords: Cardiac hypertrophy; G protein-coupled receptors; GRK2; Heart failure; High fat diet; Insulin resistance