期刊
BASIC RESEARCH IN CARDIOLOGY
卷 105, 期 2, 页码 289-300出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-009-0053-z
关键词
Protein kinase C; Cardiac; Heart failure; Myofilament function; Contractile proteins; Phosphorylation
Previous studies indicated that the increase in protein kinase C (PKC)-mediated myofilament protein phosphorylation observed in failing myocardium might be detrimental for contractile function. This study was designed to reveal and compare the effects of PKC alpha- and PKC epsilon-mediated phosphorylation on myofilament function in human myocardium. Isometric force was measured at different [Ca2+] in single permeabilized cardiomyocytes from failing human left ventricular tissue. Activated PKC alpha and PKC epsilon equally reduced Ca2+ sensitivity in failing cardiomyocytes (Delta pCa(50) = 0.08 +/- A 0.01). Both PKC isoforms increased phosphorylation of troponin I- (cTnI) and myosin binding protein C (cMyBP-C) in failing cardiomyocytes. Subsequent incubation of failing cardiomyocytes with the catalytic subunit of protein kinase A (PKA) resulted in a further reduction in Ca2+ sensitivity, indicating that the effects of both PKC isoforms were not caused by cross-phosphorylation of PKA sites. Both isozymes showed no effects on maximal force and only PKC alpha resulted in a modest significant reduction in passive force. Effects of PKC alpha were only minor in donor cardiomyocytes, presumably because of already saturated cTnI and cMyBP-C phosphorylation levels. Donor tissue could therefore be used as a tool to reveal the functional effects of troponin T (cTnT) phosphorylation by PKC alpha. Massive dephosphorylation of cTnT with alkaline phosphatase increased Ca2+ sensitivity. Subsequently, PKC alpha treatment of donor cardiomyocytes reduced Ca2+ sensitivity (Delta pCa(50) = 0.08 +/- A 0.02) and solely increased phosphorylation of cTnT, but did not affect maximal and passive force. PKC alpha- and PKC epsilon-mediated phosphorylation of cMyBP-C and cTnI as well as cTnT decrease myofilament Ca2+ sensitivity and may thereby reduce contractility and enhance relaxation of human myocardium.
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