CaMKII effects on inotropic but not lusitropic force frequency responses require phospholamban

Yiming Wu, Elizabeth D. Luczak, Eun Jeong Lee, Carlos Hidalgo, Jinying Yang, Zhan Gao, Jingdong Li, Xander H.T. Wehrens, Hendrikus "Henk" Granzier, Mark E. Anderson

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 Ca2+/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 360beats/min to 630beats/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.

Original languageEnglish (US)
Pages (from-to)429-436
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume53
Issue number3
DOIs
StatePublished - Sep 2012

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Heart Ventricles
Myofibrils
Pressure
Heart Rate
phospholamban
Genetic Models
Myocardium
Calcium

Keywords

  • CaM kinase II
  • Force-frequency relation
  • Frequency-dependent acceleration of relaxation
  • Phospholamban

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

CaMKII effects on inotropic but not lusitropic force frequency responses require phospholamban. / Wu, Yiming; Luczak, Elizabeth D.; Lee, Eun Jeong; Hidalgo, Carlos; Yang, Jinying; Gao, Zhan; Li, Jingdong; H.T. Wehrens, Xander; Granzier, Hendrikus "Henk"; Anderson, Mark E.

In: Journal of Molecular and Cellular Cardiology, Vol. 53, No. 3, 09.2012, p. 429-436.

Research output: Contribution to journalArticle

Wu, Y, Luczak, ED, Lee, EJ, Hidalgo, C, Yang, J, Gao, Z, Li, J, H.T. Wehrens, X, Granzier, HH & Anderson, ME 2012, 'CaMKII effects on inotropic but not lusitropic force frequency responses require phospholamban', Journal of Molecular and Cellular Cardiology, vol. 53, no. 3, pp. 429-436. https://doi.org/10.1016/j.yjmcc.2012.06.019
Wu, Yiming ; Luczak, Elizabeth D. ; Lee, Eun Jeong ; Hidalgo, Carlos ; Yang, Jinying ; Gao, Zhan ; Li, Jingdong ; H.T. Wehrens, Xander ; Granzier, Hendrikus "Henk" ; Anderson, Mark E. / CaMKII effects on inotropic but not lusitropic force frequency responses require phospholamban. In: Journal of Molecular and Cellular Cardiology. 2012 ; Vol. 53, No. 3. pp. 429-436.
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abstract = "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 Ca2+/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 360beats/min to 630beats/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.",
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AU - Lee, Eun Jeong

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AU - Yang, Jinying

AU - Gao, Zhan

AU - Li, Jingdong

AU - H.T. Wehrens, Xander

AU - Granzier, Hendrikus "Henk"

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N2 - 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 Ca2+/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 360beats/min to 630beats/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.

AB - 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 Ca2+/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 360beats/min to 630beats/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.

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