RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.113.087312
DO 10.1124/mol.113.087312
A1 Jorgen Gravning
A1 Mohammed Shakil Ahmed
A1 Eirik Qvigstad
A1 Kurt A. Krobert
A1 Thor Edvardsen
A1 Ingvild Tronstad Moe
A1 Else Marie Valbjorn Hagelin
A1 Julia Sagave
A1 Guro Valen
A1 Finn Olav Levy
A1 Jan-Bjorn Osnes
A1 Tor Skomedal
A1 Havard Attramadal
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/06/18/mol.113.087312.abstract
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 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.