TY - JOUR T1 - Connective Tissue Growth Factor / Ccn2 Attenuates β-Adrenergic Receptor Responsiveness and Cardiotoxicity by Induction of G Protein-coupled Receptor Kinase-5 (Grk5) in Cardiomyocytes JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.087312 SP - mol.113.087312 AU - Jorgen Gravning AU - Mohammed Shakil Ahmed AU - Eirik Qvigstad AU - Kurt A. Krobert AU - Thor Edvardsen AU - Ingvild Tronstad Moe AU - Else Marie Valbjorn Hagelin AU - Julia Sagave AU - Guro Valen AU - Finn Olav Levy AU - Jan-Bjorn Osnes AU - Tor Skomedal AU - Havard Attramadal Y1 - 2013/01/01 UR - http://molpharm.aspetjournals.org/content/early/2013/06/18/mol.113.087312.abstract N2 - 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 fibres from Tg-CTGF mice and nontransgenic littermates (NLC) 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 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, CHO 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 mice (GRK5-KO) to β-adrenergic agonist, 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 (14 days) exposure 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. ER -