title: RGS2 inhibits beta-adrenergic receptor-induced cardiomyocyte hypertrophy.
abstract: The chronic stimulation of certain G protein-coupled receptors promotes cardiomyocyte hypertrophy and thus plays a pivotal role in the development of human heart failure. The beta-adrenergic receptors (beta-AR) are unique among these in that they signal via Gs, whereas others, such as the alpha1-adrenergic (alpha1-AR) and endothelin-1 (ET-1) receptors, predominantly act through Gq. In this study, we investigated the potential role of regulator of G protein signalling 2 (RGS2) in modulating the hypertrophic effects of the beta-AR agonist isoproterenol (ISO) in rat neonatal ventricular cardiomyocytes. We found that ISO-induced hypertrophy in rat neonatal ventricular myocytes was accompanied by the selective upregulation of RGS2 mRNA, with little or no change in RGS1, RGS3, RGS4 or RGS5. The adenylyl cyclase activator forskolin had a similar effect suggesting that it was mediated through cAMP production. To study the role of RGS2 upregulation in beta-AR-dependent hypertrophy, cardiomyocytes were infected with adenovirus encoding RGS2 and assayed for cell growth, markers of hypertrophy, and beta-AR signalling. ISO-induced increases in cell surface area were virtually eliminated by the overexpression of RGS2, as were increases in alpha-skeletal actin and atrial natriuretic peptide. RGS2 overexpression also significantly attenuated ISO-induced extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Akt activation, which may account for, or contribute to, its observed antihypertrophic effects. In contrast, RGS2 overexpression significantly activated JNK MAP kinase, while decreasing the potency but not the maximal effect of ISO on cAMP accumulation. In conclusion, the present results suggest that RGS2 negatively regulates hypertrophy induced by beta-AR activation and thus may play a protective role in cardiac hypertrophy.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nunn
authors.forename: Min-Xu
authors.initials: MX
authors.lastname: Zou
authors.forename: Alina J
authors.initials: AJ
authors.lastname: Sobiesiak
authors.forename: Anju A
authors.initials: AA
authors.lastname: Roy
authors.forename: Lorrie A
authors.initials: LA
authors.lastname: Kirshenbaum
authors.forename: Peter
authors.initials: P
authors.lastname: Chidiac
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D049108:Cell Enlargement; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000254:growth & development; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D000318:Adrenergic beta-Agonists; D019332:Endothelin-1; D020710:RGS Proteins; C514563:RGS2 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol