CaMKII effects on inotropic but not lusitropic force frequency responses require phospholamban.
Increasing heart rate enhances cardiac contractility (force frequency relationship, FFR) and accelerates cardiac relaxation (frequency-dependent acceleration of relaxation, FDAR). The positive FFR together with FDAR promotes rapid filling and ejection of blood from the left ventricle (LV) at higher heart rates. Recent studies indicate that the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is involved in regulating FFR and FDAR. We used isolated perfused mouse hearts to study the mechanisms of FFR and FDAR in different genetic models, including transgenic myocardial CaMKII inhibition (AC3-I) and phospholmban knockout (PLN(-/-)). When the rate was increased from 360 beats/min to 630 beats/min in wild type mouse hearts, the LV developed pressure (LVDP) and the maximum rate of increase in pressure (dP/dt max) increased by 37.6 ± 4.7% and 77.0 ± 8.1%, respectively. However, hearts from AC3-I littermates showed no increase of LVDP and a relatively modest (20.4 ± 3.9%) increase in dP/dt max. PLN(-/-) hearts had a negative FFR, and myocardial AC3-I expression did not change the FFR in PLN(-/-) mice. PLN(-/-) mouse hearts did not exhibit FDAR, while PLN(-/-) mice with myocardial AC3-I expression showed further frequency dependent reductions in cardiac relaxation, suggesting that CaMKII targets in addition to PLN were critical to myocardial relaxation. We incubated a constitutively active form of CaMKII with chemically-skinned myocardium and found that several myofilament proteins were phosphorylated by CaMKII. However, CaMKII did not affect myofilament calcium sensitivity. Our study shows that CaMKII plays an important role in modulating FFR and FDAR in murine hearts and suggest that PLN is a critical target for CaMKII effects on FFR, while CaMKII effects on FDAR partially require PLN-alternative targets.
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1081, USA.
Yiming
Y
Wu
Elizabeth D
ED
Luczak
Eun-Jeong
EJ
Lee
Carlos
C
Hidalgo
Jinying
J
Yang
Zhan
Z
Gao
Jingdong
J
Li
Xander H T
XH
Wehrens
Henk
H
Granzier
Mark E
ME
Anderson
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006321:Heart / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism; D010766:Phosphorylation; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000099211:Phospholamban