title: Prevention of myofilament dysfunction by beta-blocker therapy in postinfarct remodeling.
abstract: BACKGROUND
  Myofilament contractility of individual cardiomyocytes is depressed in remote noninfarcted myocardium and contributes to global left ventricular pump dysfunction after myocardial infarction (MI). Here, we investigated whether beta-blocker therapy could restore myofilament contractility.
  
  
  RESULTS
  In pigs with a MI induced by ligation of the left circumflex coronary artery, beta-blocker therapy (bisoprolol, MI+beta) was initiated on the first day after MI. Remote left ventricular subendocardial biopsies were taken 3 weeks after sham or MI surgery. Isometric force was measured in single permeabilized cardiomyocytes. Maximal force (F(max)) was lower, whereas Ca(2+) sensitivity was higher in untreated MI compared with sham (both P<0.05). The difference in Ca(2+) sensitivity was abolished by treatment of cells with the beta-adrenergic kinase, protein kinase A. beta-blocker therapy partially reversed F(max) and Ca(2+) sensitivity to sham values and significantly reduced passive force. Despite the lower myofilament Ca(2+) sensitivity in MI+beta compared with untreated myocardium, the protein kinase A induced reduction in Ca(2+) sensitivity was largest in cardiomyocytes from myocardium treated with beta-blockers. Phosphorylation of beta-adrenergic target proteins (myosin binding protein C and troponin I) did not differ among groups, whereas myosin light chain 2 phosphorylation was reduced in MI, which coincided with increased expression of protein phosphatase 1. beta-blockade fully restored the latter alterations and significantly reduced expression of protein phosphatase 2a.
  
  
  CONCLUSIONS
  beta-blockade reversed myofilament dysfunction and enhanced myofilament responsiveness to protein kinase A in remote myocardium after MI. These effects likely contribute to the beneficial effects of beta-blockade on global left ventricular function after MI.
authors.affiliation: Department of Biochemistry, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, Thoraxcenter, Rotterdam, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.forename: Nicky M
authors.initials: NM
authors.lastname: Boontje
authors.forename: Daphne
authors.initials: D
authors.lastname: Merkus
authors.forename: Amanda
authors.initials: A
authors.lastname: Versteilen
authors.forename: Judith
authors.initials: J
authors.lastname: Krysiak
authors.forename: Giulia
authors.initials: G
authors.lastname: Mearini
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: de Beer
authors.forename: Jos M J
authors.initials: JM
authors.lastname: Lamers
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Lori A
authors.initials: LA
authors.lastname: Walker
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017298:Bisoprolol / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D024722:Cardiac Myosins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D064211:Connectin; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D020127:Recovery of Function; D013552:Swine; D013997:Time Factors; D019210:Troponin I / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects*; D000099163:Myosin Binding Protein C
chemical_list: D000319:Adrenergic beta-Antagonists; D017298:Bisoprolol; D024722:Cardiac Myosins; D002352:Carrier Proteins; D064211:Connectin; D017868:Cyclic AMP-Dependent Protein Kinases; D009124:Muscle Proteins; D018994:Myosin Light Chains; D011494:Protein Kinases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D019210:Troponin I; D000099163:Myosin Binding Protein C; C107184:myosin light chain 2