title: Endothelin-1 and isoprenaline co-stimulation causes contractile failure which is partially reversed by MEK inhibition.
abstract: OBJECTIVE
  The mitogen-activated kinase kinases (MEK)-extracellular signal-regulated kinases (ERK) signaling pathway is activated by agonists like catecholamines or endothelin-1 (ET-1) and has been implicated in cardiac pathology, such as the progression from cardiac hypertrophy to failure. The purpose of the present study, performed in an in vitro model of contractile failure, was to evaluate whether MEK inhibition prevents functional deterioration.
  
  
  RESULTS
  Contractile dysfunction was induced in reconstituted rat heart tissue by concomitant treatment with ET-1 (10 nmol/l) and isoprenaline (ISO, 10 nmol/l) for 5 days. While basal force of contraction was unchanged, contractile responsiveness to beta-adrenoceptor agonists was markedly impaired (active force declined to 51% of controls) and was associated with decreased lusitropy. Moreover, in ET-1+ISO-treated heart tissues, reprogramming of gene expression was observed with an increased ratio of beta-myosin heavy chain (MHC) to alpha-MHC mRNA and increased transcript levels of ANF and skeletal/smooth muscle alpha-actin isoforms. The MEK inhibitor U0126 (10 micromol/l) almost completely prevented the reduction in beta-adrenergic responsiveness and the negative lusitropic effect of ET-1+ISO co-stimulation. In addition, U0126 completely normalized ANF gene expression, but did not affect or only marginally affected expression of MHC and alpha-actin isoforms.
  
  
  CONCLUSIONS
  These results suggest that interruption of the MEK-ERK signaling pathway with a specific MEK inhibitor prevents, in part, the occurrence of a pathologic phenotype secondary to excessive stimulation with neurohumoral factors. The MEK-ERK pathway seems to be an important but not exclusive regulatory pathway responsible for the development of contractile dysfunction.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Münzel
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mühlhäuser
authors.forename: Wolfram-Hubertus
authors.initials: WH
authors.lastname: Zimmermann
authors.forename: Michael
authors.initials: M
authors.lastname: Didié
authors.forename: Karin
authors.initials: K
authors.lastname: Schneiderbanger
authors.forename: Pia
authors.initials: P
authors.lastname: Schubert
authors.forename: Sven
authors.initials: S
authors.lastname: Engmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
mesh_terms: D000199:Actins / Q000032:analysis / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000032:analysis / Q000235:genetics; D002070:Butadienes / Q000627:therapeutic use*; D003864:Depression, Chemical; D019332:Endothelin-1 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced* / Q000188:drug therapy; D007545:Isoproterenol / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D009570:Nitriles / Q000627:therapeutic use*; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D023822:Tissue Engineering
chemical_list: D000199:Actins; D002070:Butadienes; D019332:Endothelin-1; C000594638:MYH7 protein, rat; D009570:Nitriles; D020033:Protein Isoforms; D012333:RNA, Messenger; C113580:U 0126; D009320:Atrial Natriuretic Factor; D020929:Mitogen-Activated Protein Kinase Kinases; D018995:Myosin Heavy Chains; D007545:Isoproterenol