title: The function of calcineurin and ERK1/2 signal in the antihypertrophic effects of kappa-opioid receptor stimulation on myocardial hypertrophy induced by isoprenaline.
abstract: The aim of the present study, performed in an in vitro model of cardiac hypertrophy, was to examine the possible function of calcineurin and ERK1/2 in the inhibitory effects of kappa-opioid receptor stimulation on Ca2+ transients and myocardial hypertrophy induced by beta1-adrenoceptor stimulation. We determined the effects of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid methanesulfonate salt (U50,488H), a selective kappa-opioid receptor agonist, on the enhancement of spontaneous Ca2+ transients and the induction of hypertrophy by isoprenaline, a beta-adrenoceptor agonist, in cultured neonatal ventricular myocytes. Total protein content, [3H]leucine incorporation and cell size were used as indices of hypertrophy; calcineurin activity and phospho-ERK1/2 level were determined by immunoblotting. Isoprenaline (10 micromol x L(-1)) increased all the three indices of hypertrophy, Ca2+ transients, calcineurin activity and the level of phospho-ERK1/2. The effects of isoprenaline were abolished by 1 micromol x L(-1) U50,488H in the absence but not in the presence of nor-binaltorphimine, a kappa-opioid receptor antagonist. The inhibitory effects of U50,488H were reproduced by cyclosporine-A, an inhibitor of calcineurin, U0126, the inhibitor of ERK1/2 and verapamil, a L-type Ca2+ channel antagonist. In addition, suppression of calcineurin activity by cyclosporine-A was associated with modest suppression of ERK1/2 phosphorylation. Meanwhile, suppression of ERK1/2 phosphorylation by U0126 was associated with modest suppression of calcineurin activity. In conclusion, the inhibitory effects of kappa-opioid receptor stimulation involved calcineurin and ERK1/2, and the two signaling pathways showed interaction in the mechanism of antihypertrophic effects afforded by kappa-opioid receptor stimulation.
authors.affiliation: Key Laboratory of Molecular Biology & Drug Research, Liaoning Medical College, Liaoning, China.
authors.forename: Meili
authors.initials: M
authors.lastname: Lu
authors.forename: Hongxin
authors.initials: H
authors.lastname: Wang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Yang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Chunna
authors.initials: C
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Tak Ming
authors.initials: TM
authors.lastname: Wong
mesh_terms: D000318:Adrenergic beta-Agonists / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy* / Q000503:physiopathology; D048429:Cell Size / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D016257:Fura-2 / Q000031:analogs & derivatives; D007249:Inflammation / Q000473:pathology; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007930:Leucine / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: D000318:Adrenergic beta-Agonists; D011506:Proteins; D017473:Receptors, Opioid, kappa; C049925:fura-2-am; D019703:Calcineurin; D007930:Leucine; D007545:Isoproterenol; D016257:Fura-2