Frequency-dependent acceleration of relaxation in the heart depends on CamKII, but not phospholamban

Jaime DeSantiago, Lars S. Maier, Donald M Bers

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Frequency-dependent acceleration of relaxation (FDAR) is an intrinsic physiological mechanism, which allows more rapid ventricular diastolic filling at higher heart rates. FDAR is also observed in isolated myocardial trabeculae and cardiac myocytes, but its mechanism is still poorly understood. We tested the hypothesis that FDAR results mainly from Ca/calmodulin-dependent protein kinase II (CaMKII) dependent stimulation of sarcoplasmic reticulum (SR) Ca transport, but does not require phospholamban. Experiments were performed at 23 or 35°C in isolated ventricular muscle and single myocytes from wild-type (WT) and phospholamban knockout (PLB-KO) mice and rat ventricular myocytes. Isometric twitch force of muscles and unloaded shortening and Ca transients in myocytes were measured ([Ca]o = 1 mM) in the absence and presence of CaMKII inhibitors (1 μM KN-93 or 20 μM autocamtide-2 related inhibitory peptide, AIP). Stimulation frequency was altered over a wide range (0.2-8 Hz) and post-rest vs steady state twitches were also compared. In both WT and PLB-KO mouse muscles FDAR of twitch force was prominent, but was largely suppressed by KN-93. FDAR of twitch contractions was associated with FDAR of Ca transients in PLB-KO myocytes, and both were inhibited by KN-93. Similarly, a different CaMKII inhibitor (AIP) inhibited FDAR of contraction and Ca transients in rat ventricular myocytes. We conclude that FDAR results mainly from CaMKII-dependent stimulation of SR Ca transport, but does not require phospholamban.

Original languageEnglish (US)
Pages (from-to)975-984
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume34
Issue number8
DOIs
StatePublished - Aug 1 2002
Externally publishedYes

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Muscle Cells
Sarcoplasmic Reticulum
Protein Kinase Inhibitors
Knockout Mice
Muscles
phospholamban
Cardiac Myocytes
Heart Rate
Peptides
KN 93

Keywords

  • CaMKII
  • Force-frequency relation
  • Phospholamban
  • Postrest-behavior
  • Relaxation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Frequency-dependent acceleration of relaxation in the heart depends on CamKII, but not phospholamban. / DeSantiago, Jaime; Maier, Lars S.; Bers, Donald M.

In: Journal of Molecular and Cellular Cardiology, Vol. 34, No. 8, 01.08.2002, p. 975-984.

Research output: Contribution to journalArticle

@article{91c99f42622c49b09eb83982919c008b,
title = "Frequency-dependent acceleration of relaxation in the heart depends on CamKII, but not phospholamban",
abstract = "Frequency-dependent acceleration of relaxation (FDAR) is an intrinsic physiological mechanism, which allows more rapid ventricular diastolic filling at higher heart rates. FDAR is also observed in isolated myocardial trabeculae and cardiac myocytes, but its mechanism is still poorly understood. We tested the hypothesis that FDAR results mainly from Ca/calmodulin-dependent protein kinase II (CaMKII) dependent stimulation of sarcoplasmic reticulum (SR) Ca transport, but does not require phospholamban. Experiments were performed at 23 or 35°C in isolated ventricular muscle and single myocytes from wild-type (WT) and phospholamban knockout (PLB-KO) mice and rat ventricular myocytes. Isometric twitch force of muscles and unloaded shortening and Ca transients in myocytes were measured ([Ca]o = 1 mM) in the absence and presence of CaMKII inhibitors (1 μM KN-93 or 20 μM autocamtide-2 related inhibitory peptide, AIP). Stimulation frequency was altered over a wide range (0.2-8 Hz) and post-rest vs steady state twitches were also compared. In both WT and PLB-KO mouse muscles FDAR of twitch force was prominent, but was largely suppressed by KN-93. FDAR of twitch contractions was associated with FDAR of Ca transients in PLB-KO myocytes, and both were inhibited by KN-93. Similarly, a different CaMKII inhibitor (AIP) inhibited FDAR of contraction and Ca transients in rat ventricular myocytes. We conclude that FDAR results mainly from CaMKII-dependent stimulation of SR Ca transport, but does not require phospholamban.",
keywords = "CaMKII, Force-frequency relation, Phospholamban, Postrest-behavior, Relaxation",
author = "Jaime DeSantiago and Maier, {Lars S.} and Bers, {Donald M}",
year = "2002",
month = "8",
day = "1",
doi = "10.1006/jmcc.2002.2034",
language = "English (US)",
volume = "34",
pages = "975--984",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
number = "8",

}

TY - JOUR

T1 - Frequency-dependent acceleration of relaxation in the heart depends on CamKII, but not phospholamban

AU - DeSantiago, Jaime

AU - Maier, Lars S.

AU - Bers, Donald M

PY - 2002/8/1

Y1 - 2002/8/1

N2 - Frequency-dependent acceleration of relaxation (FDAR) is an intrinsic physiological mechanism, which allows more rapid ventricular diastolic filling at higher heart rates. FDAR is also observed in isolated myocardial trabeculae and cardiac myocytes, but its mechanism is still poorly understood. We tested the hypothesis that FDAR results mainly from Ca/calmodulin-dependent protein kinase II (CaMKII) dependent stimulation of sarcoplasmic reticulum (SR) Ca transport, but does not require phospholamban. Experiments were performed at 23 or 35°C in isolated ventricular muscle and single myocytes from wild-type (WT) and phospholamban knockout (PLB-KO) mice and rat ventricular myocytes. Isometric twitch force of muscles and unloaded shortening and Ca transients in myocytes were measured ([Ca]o = 1 mM) in the absence and presence of CaMKII inhibitors (1 μM KN-93 or 20 μM autocamtide-2 related inhibitory peptide, AIP). Stimulation frequency was altered over a wide range (0.2-8 Hz) and post-rest vs steady state twitches were also compared. In both WT and PLB-KO mouse muscles FDAR of twitch force was prominent, but was largely suppressed by KN-93. FDAR of twitch contractions was associated with FDAR of Ca transients in PLB-KO myocytes, and both were inhibited by KN-93. Similarly, a different CaMKII inhibitor (AIP) inhibited FDAR of contraction and Ca transients in rat ventricular myocytes. We conclude that FDAR results mainly from CaMKII-dependent stimulation of SR Ca transport, but does not require phospholamban.

AB - Frequency-dependent acceleration of relaxation (FDAR) is an intrinsic physiological mechanism, which allows more rapid ventricular diastolic filling at higher heart rates. FDAR is also observed in isolated myocardial trabeculae and cardiac myocytes, but its mechanism is still poorly understood. We tested the hypothesis that FDAR results mainly from Ca/calmodulin-dependent protein kinase II (CaMKII) dependent stimulation of sarcoplasmic reticulum (SR) Ca transport, but does not require phospholamban. Experiments were performed at 23 or 35°C in isolated ventricular muscle and single myocytes from wild-type (WT) and phospholamban knockout (PLB-KO) mice and rat ventricular myocytes. Isometric twitch force of muscles and unloaded shortening and Ca transients in myocytes were measured ([Ca]o = 1 mM) in the absence and presence of CaMKII inhibitors (1 μM KN-93 or 20 μM autocamtide-2 related inhibitory peptide, AIP). Stimulation frequency was altered over a wide range (0.2-8 Hz) and post-rest vs steady state twitches were also compared. In both WT and PLB-KO mouse muscles FDAR of twitch force was prominent, but was largely suppressed by KN-93. FDAR of twitch contractions was associated with FDAR of Ca transients in PLB-KO myocytes, and both were inhibited by KN-93. Similarly, a different CaMKII inhibitor (AIP) inhibited FDAR of contraction and Ca transients in rat ventricular myocytes. We conclude that FDAR results mainly from CaMKII-dependent stimulation of SR Ca transport, but does not require phospholamban.

KW - CaMKII

KW - Force-frequency relation

KW - Phospholamban

KW - Postrest-behavior

KW - Relaxation

UR - http://www.scopus.com/inward/record.url?scp=0036702654&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036702654&partnerID=8YFLogxK

U2 - 10.1006/jmcc.2002.2034

DO - 10.1006/jmcc.2002.2034

M3 - Article

C2 - 12234767

AN - SCOPUS:0036702654

VL - 34

SP - 975

EP - 984

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

IS - 8

ER -