PT - JOURNAL ARTICLE AU - Gravning, Jørgen AU - Ahmed, M. Shakil AU - Qvigstad, Eirik AU - Krobert, Kurt AU - Edvardsen, Thor AU - Moe, Ingvild Tronstad AU - Hagelin, Else Marie V. AU - Sagave, Julia AU - Valen, Guro AU - Levy, Finn Olav AU - Osnes, Jan-Bjørn AU - Skomedal, Tor AU - Attramadal, Håvard TI - Connective Tissue Growth Factor/CCN2 Attenuates <em>β</em>-Adrenergic Receptor Responsiveness and Cardiotoxicity by Induction of G Protein–Coupled Receptor Kinase-5 in Cardiomyocytes AID - 10.1124/mol.113.087312 DP - 2013 Sep 01 TA - Molecular Pharmacology PG - 372--383 VI - 84 IP - 3 4099 - http://molpharm.aspetjournals.org/content/84/3/372.short 4100 - http://molpharm.aspetjournals.org/content/84/3/372.full SO - Mol Pharmacol2013 Sep 01; 84 AB - 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.