Control of in vivo left ventricular [correction] contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation.
BACKGROUND
Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament protein whose presence and phosphorylation by protein kinase A (PKA) regulates cross-bridge formation and kinetics in isolated myocardium. We tested the influence of cMyBP-C and its PKA-phosphorylation on contraction/relaxation kinetics in intact hearts and revealed its essential role in several classic properties of cardiac function.


RESULTS
Comprehensive in situ cardiac pressure-volume analysis was performed in mice harboring a truncation mutation of cMyBP-C (cMyBP-C(t/t)) that resulted in nondetectable protein versus hearts re-expressing solely wild-type (cMyBP-C(WT:(t/t))) or mutated protein in which known PKA-phosphorylation sites were constitutively suppressed (cMyBP-C(AllP-:(t/t))). Hearts lacking cMyBP-C had faster early systolic activation, which then terminated prematurely, limiting ejection. Systole remained short at faster heart rates; thus, cMyBP-C(t/t) hearts displayed minimal rate-dependent decline in diastolic time and cardiac preload. Furthermore, prolongation of pressure relaxation by afterload was markedly blunted in cMyBP-C(t/t) hearts. All 3 properties were similarly restored to normal in cMyBP-C(WT:(t/t)) and cMyBP-C(AllP-:(t/t)) hearts, which supports independence of PKA-phosphorylation. However, the dependence of peak rate of pressure rise on preload was specifically depressed in cMyBP-C(AllP-:(t/t)) hearts, whereas cMyBP-C(t/t) and cMyBP-C(AllP-:(t/t)) hearts had similar blunted adrenergic and rate-dependent contractile reserve, which supports linkage of these behaviors to PKA-cMyBP-C modification.


CONCLUSIONS
cMyBP-C is essential for major properties of cardiac function, including sustaining systole during ejection, the heart-rate dependence of the diastolic time period, and relaxation delay from increased arterial afterload. These are independent of its phosphorylation by PKA, which more specifically modulates early pressure rise rate and adrenergic/heart rate reserve.
Nagayama
Takahiro
T
Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Takimoto
Eiki
E
Sadayappan
Sakthivel
S
Mudd
James O
JO
Seidman
J G
JG
Robbins
Jeffrey
J
Kass
David A
DA
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D003971:Diastole / Q000235:genetics / Q000502:physiology; D005260:Female; D006339:Heart Rate / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D013599:Systole / Q000235:genetics / Q000502:physiology; D016277:Ventricular Function, Left / Q000235:genetics / Q000502:physiology; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D000099163:Myosin Binding Protein C