Prevention of myofilament dysfunction by beta-blocker therapy in postinfarct remodeling.
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.
Duncker
Dirk J
DJ
Department of Biochemistry, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, Thoraxcenter, Rotterdam, The Netherlands.
Boontje
Nicky M
NM
Merkus
Daphne
D
Versteilen
Amanda
A
Krysiak
Judith
J
Mearini
Giulia
G
El-Armouche
Ali
A
de Beer
Vincent J
VJ
Lamers
Jos M J
JM
Carrier
Lucie
L
Walker
Lori A
LA
Linke
Wolfgang A
WA
Stienen
Ger J M
GJ
van der Velden
Jolanda
J
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
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