title: Chronic cardiotrophin-1 stimulation impairs contractile function in reconstituted heart tissue.
abstract: Cardiotrophin-1 (CT-1) is known to promote survival but also to induce an elongated morphology of isolated cardiac myocytes, leading to the hypothesis that CT-1, which is chronically augmented in human heart failure, might induce eccentric cardiac hypertrophy and contractile failure. To address this, we used heart tissues reconstituted from neonatal rat cardiac myocytes (engineered heart tissue, EHT) as multicellular in vitro test systems. CT-1 dose-dependently affected contractile function in EHTs. After treatment with 0.1 nM CT-1 (corresponds to plasma levels in humans) for 10 days, twitch tension significantly decreased to 0.30 +/- 0.04 mN (n = 15) vs. 0.45 +/- 0.04 mN (n = 16) in controls. Furthermore, positive inotropic effects of cumulative concentrations of Ca2+ and isoprenaline were significantly diminished. Maximum isoprenaline-induced increase in twitch tension amounted to 0.27 +/- 0.04 mN (n = 15) vs. 0.47 +/- 0.06 mN (n = 16) in controls (P < 0.001). When EHTs were treated for only 5 days, qualitatively similar results were obtained but changes were less pronounced. Immunostaining of whole mount EHT preparations revealed that after CT-1 treatment, the number of nonmyocytes significantly increased by 98% (1 nM, 10 days), and myocytes did not form compact, longitudinally oriented muscle bundles. Interestingly, expression of the Ca2+-handling protein calsequestrin was markedly reduced (69 +/- 7% of control) by treatment with CT-1 (0.1 nM, 10 days). In summary, long-term exposure to CT-1 induces contractile dysfunction in EHTs. Structural changes due to impaired differentiation and/or remodeling of heart tissue may play an important role.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054 Erlangen, Germany. zolk@pharmakologie.uni-erlangen.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
authors.forename: Sven
authors.initials: S
authors.lastname: Engmann
authors.forename: Felix
authors.initials: F
authors.lastname: Münzel
authors.forename: Rasti
authors.initials: R
authors.lastname: Krajcik
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D018613:Microscopy, Confocal; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D023822:Tissue Engineering; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D002155:Calsequestrin; D002316:Cardiotonic Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; C092073:cardiotrophin 1; D007545:Isoproterenol; D002118:Calcium