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Research ArticleArticle

Connective Tissue Growth Factor/CCN2 Attenuates β-Adrenergic Receptor Responsiveness and Cardiotoxicity by Induction of G Protein–Coupled Receptor Kinase-5 in Cardiomyocytes

Jørgen Gravning, M. Shakil Ahmed, Eirik Qvigstad, Kurt Krobert, Thor Edvardsen, Ingvild Tronstad Moe, Else Marie V. Hagelin, Julia Sagave, Guro Valen, Finn Olav Levy, Jan-Bjørn Osnes, Tor Skomedal and Håvard Attramadal
Molecular Pharmacology September 2013, 84 (3) 372-383; DOI: https://doi.org/10.1124/mol.113.087312
Jørgen Gravning
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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M. Shakil Ahmed
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Eirik Qvigstad
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Kurt Krobert
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Thor Edvardsen
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Ingvild Tronstad Moe
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Else Marie V. Hagelin
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Julia Sagave
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Guro Valen
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Finn Olav Levy
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Jan-Bjørn Osnes
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Tor Skomedal
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Håvard Attramadal
Institute for Surgical Research (J.G., M.S.A., I.T.M., E.M.V.H., H.A.) and Departments of Cardiology (H.A., T.E.) and Pharmacology (E.Q., K.K., F.O.L., J.-B.O., T.S.), Oslo University Hospital and University of Oslo, Oslo, Norway; and Center for Heart Failure Research (J.G., M.S.A., E.Q., K.K., T.E., I.T.M., E.M.V.H., G.V., F.O.L., J.-B.O., T.S., H.A.), K. G. Jebsen Cardiac Research Centre (E.Q., K.K., F.O.L., J.-B.O., T.S.), and Department of Physiology (J.S., G.V.), University of Oslo, Oslo, Norway
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Abstract

Myocardial connective tissue growth factor (CTGF/CCN2) is induced in heart failure, a condition associated with diminution of β-adrenergic receptor (β-AR) responsiveness. Accordingly, we aimed to investigate whether CTGF could play a mechanistic role in regulation of β-AR responsiveness. Concentration-response curves of isoproterenol-stimulated cAMP generation in cardiomyocytes from transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) or cardiomyocytes pretreated with recombinant human CTGF (rec-hCTGF) revealed marked reduction of both β1-AR and β2-AR responsiveness. Consistently, ventricular muscle strips from Tg-CTGF mice stimulated with isoproterenol displayed attenuation of maximal inotropic responses. However, no differences of maximal inotropic responses of myocardial fibers from Tg-CTGF mice and nontransgenic littermate control (NLC) mice were discerned when stimulated with supramaximal concentrations of dibutyryl-cAMP, indicating preserved downstream responsiveness to cAMP. Congruent with a mechanism of desensitization of β-ARs, mRNA and protein levels of G protein–coupled receptor kinase 5 (GRK5) were found isoform-selective upregulated in both cardiomyocytes from Tg-CTGF mice and cardiomyocytes exposed to rec-hCTGF. Corroborating a mechanism of GRK5 in CTGF-mediated control of β-AR sensitivity, Chinese hamster ovary cells pretreated with rec-hCTGF displayed increased agonist- and biased ligand-stimulated β-arrestin binding to β-ARs. Despite increased sensitivity of cardiomyocytes from GRK5-knockout (KO) mice to β-adrenergic agonists, pretreatment of GRK5-KO cardiomyocytes with rec-hCTGF, as opposed to cardiomyocytes from wild-type mice, did not alter β-AR responsiveness. Finally, Tg-CTGF mice subjected to chronic exposure (14 days) to isoproterenol revealed blunted myocardial hypertrophy and preserved cardiac function versus NLC mice. In conclusion, this study uncovers a novel mechanism controlling β-AR responsiveness in cardiomyocytes involving CTGF-mediated regulation of GRK5.

Footnotes

    • Received May 11, 2013.
    • Accepted June 18, 2013.
  • This work was supported by the South-Eastern Norway Regional Health Authority [Grants 2009086 and 2011006]; the Norwegian Council on Cardiovascular Disease [Grant 6484]; and the Norwegian Research Council [Grant 170463/V40].

  • dx.doi.org/ 10.1124/mol.113.087312.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (3)
Molecular Pharmacology
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1 Sep 2013
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Research ArticleArticle

CTGF-Induced Desensitization of β-ARs

Jørgen Gravning, M. Shakil Ahmed, Eirik Qvigstad, Kurt Krobert, Thor Edvardsen, Ingvild Tronstad Moe, Else Marie V. Hagelin, Julia Sagave, Guro Valen, Finn Olav Levy, Jan-Bjørn Osnes, Tor Skomedal and Håvard Attramadal
Molecular Pharmacology September 1, 2013, 84 (3) 372-383; DOI: https://doi.org/10.1124/mol.113.087312

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Research ArticleArticle

CTGF-Induced Desensitization of β-ARs

Jørgen Gravning, M. Shakil Ahmed, Eirik Qvigstad, Kurt Krobert, Thor Edvardsen, Ingvild Tronstad Moe, Else Marie V. Hagelin, Julia Sagave, Guro Valen, Finn Olav Levy, Jan-Bjørn Osnes, Tor Skomedal and Håvard Attramadal
Molecular Pharmacology September 1, 2013, 84 (3) 372-383; DOI: https://doi.org/10.1124/mol.113.087312
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