The effect of myosin light chain 2 dephosphorylation on Ca2+-sensitivity of force is enhanced in failing human hearts

J. Van Der Velden, Z. Papp, N. M. Boontje, R. Zaremba, J. W. De Jong, P. M.L. Janssen, G. Hasenfuss, G. J.M. Stienen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Objective: Phosphorylation of the myosin light chain 2 (MLC-2) isoform expressed as a percentage of total MLC-2 was decreased in failing (21.1±2.0%) compared to donor (31.9±4.8%) hearts. To assess the functional implications of this change, we compared the effects of MLC-2 dephosphorylation on force development in failing and non-failing (donor) human hearts. Methods: Cooperative effects in isometric force and rate of force redevelopment (Ktr) were studied in single Triton-skinned human cardiomyocytes at various [Ca2+] before and after protein phosphatase-1 (PP-1) incubation. Results: Maximum force and Ktr values did not differ between failing and donor hearts, but Ca2+-sensitivity of force (pCa50) was significantly higher in failing myocardium (ΔpCa50=0.17). Ktr decreased with decreasing [Ca2+], although this decrease was less in failing than in donor hearts. Incubation of the myocytes with PP-1 (0.5 U/ml; 60 min) decreased pCa50 to a larger extent in failing (0.20 pCa units) than in donor cardiomyocytes (0.10 pCa units). A decrease in absolute Ktr values was found after PP-1 in failing and donor myocytes, while the shape of the Ktr-Ca2+ relationships remained unaltered. Conclusions: Surprisingly, the contractile response to MLC-2 dephosphorylation is enhanced in failing hearts, despite the reduced level of basal MLC-2 phosphorylation. The enhanced response to MLC-2 dephosphorylation in failing myocytes might result from differences in basal phosphorylation of other thin and thick filament proteins between donor and failing hearts. Regulation of Ca2+-sensitivity via MLC-2 phosphorylation may be a potential compensatory mechanism to reverse the detrimental effects of increased Ca2+-sensitivity and impaired Ca2+-handling on diastolic function in human heart failure.

Original languageEnglish
Pages (from-to)505-514
Number of pages10
JournalCardiovascular Research
Volume57
Issue number2
DOIs
Publication statusPublished - 1 Feb 2003

Cite this

Van Der Velden, J. ; Papp, Z. ; Boontje, N. M. ; Zaremba, R. ; De Jong, J. W. ; Janssen, P. M.L. ; Hasenfuss, G. ; Stienen, G. J.M. / The effect of myosin light chain 2 dephosphorylation on Ca2+-sensitivity of force is enhanced in failing human hearts. In: Cardiovascular Research. 2003 ; Vol. 57, No. 2. pp. 505-514.
@article{ad860e0fc0404a67b3482b6585a3c351,
title = "The effect of myosin light chain 2 dephosphorylation on Ca2+-sensitivity of force is enhanced in failing human hearts",
abstract = "Objective: Phosphorylation of the myosin light chain 2 (MLC-2) isoform expressed as a percentage of total MLC-2 was decreased in failing (21.1±2.0{\%}) compared to donor (31.9±4.8{\%}) hearts. To assess the functional implications of this change, we compared the effects of MLC-2 dephosphorylation on force development in failing and non-failing (donor) human hearts. Methods: Cooperative effects in isometric force and rate of force redevelopment (Ktr) were studied in single Triton-skinned human cardiomyocytes at various [Ca2+] before and after protein phosphatase-1 (PP-1) incubation. Results: Maximum force and Ktr values did not differ between failing and donor hearts, but Ca2+-sensitivity of force (pCa50) was significantly higher in failing myocardium (ΔpCa50=0.17). Ktr decreased with decreasing [Ca2+], although this decrease was less in failing than in donor hearts. Incubation of the myocytes with PP-1 (0.5 U/ml; 60 min) decreased pCa50 to a larger extent in failing (0.20 pCa units) than in donor cardiomyocytes (0.10 pCa units). A decrease in absolute Ktr values was found after PP-1 in failing and donor myocytes, while the shape of the Ktr-Ca2+ relationships remained unaltered. Conclusions: Surprisingly, the contractile response to MLC-2 dephosphorylation is enhanced in failing hearts, despite the reduced level of basal MLC-2 phosphorylation. The enhanced response to MLC-2 dephosphorylation in failing myocytes might result from differences in basal phosphorylation of other thin and thick filament proteins between donor and failing hearts. Regulation of Ca2+-sensitivity via MLC-2 phosphorylation may be a potential compensatory mechanism to reverse the detrimental effects of increased Ca2+-sensitivity and impaired Ca2+-handling on diastolic function in human heart failure.",
keywords = "Cardiomyopathy, Contractile apparatus, Contractile function, Myocytes, Signal transduction",
author = "{Van Der Velden}, J. and Z. Papp and Boontje, {N. M.} and R. Zaremba and {De Jong}, {J. W.} and Janssen, {P. M.L.} and G. Hasenfuss and Stienen, {G. J.M.}",
year = "2003",
month = "2",
day = "1",
doi = "10.1016/S0008-6363(02)00662-4",
language = "English",
volume = "57",
pages = "505--514",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "2",

}

The effect of myosin light chain 2 dephosphorylation on Ca2+-sensitivity of force is enhanced in failing human hearts. / Van Der Velden, J.; Papp, Z.; Boontje, N. M.; Zaremba, R.; De Jong, J. W.; Janssen, P. M.L.; Hasenfuss, G.; Stienen, G. J.M.

In: Cardiovascular Research, Vol. 57, No. 2, 01.02.2003, p. 505-514.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The effect of myosin light chain 2 dephosphorylation on Ca2+-sensitivity of force is enhanced in failing human hearts

AU - Van Der Velden, J.

AU - Papp, Z.

AU - Boontje, N. M.

AU - Zaremba, R.

AU - De Jong, J. W.

AU - Janssen, P. M.L.

AU - Hasenfuss, G.

AU - Stienen, G. J.M.

PY - 2003/2/1

Y1 - 2003/2/1

N2 - Objective: Phosphorylation of the myosin light chain 2 (MLC-2) isoform expressed as a percentage of total MLC-2 was decreased in failing (21.1±2.0%) compared to donor (31.9±4.8%) hearts. To assess the functional implications of this change, we compared the effects of MLC-2 dephosphorylation on force development in failing and non-failing (donor) human hearts. Methods: Cooperative effects in isometric force and rate of force redevelopment (Ktr) were studied in single Triton-skinned human cardiomyocytes at various [Ca2+] before and after protein phosphatase-1 (PP-1) incubation. Results: Maximum force and Ktr values did not differ between failing and donor hearts, but Ca2+-sensitivity of force (pCa50) was significantly higher in failing myocardium (ΔpCa50=0.17). Ktr decreased with decreasing [Ca2+], although this decrease was less in failing than in donor hearts. Incubation of the myocytes with PP-1 (0.5 U/ml; 60 min) decreased pCa50 to a larger extent in failing (0.20 pCa units) than in donor cardiomyocytes (0.10 pCa units). A decrease in absolute Ktr values was found after PP-1 in failing and donor myocytes, while the shape of the Ktr-Ca2+ relationships remained unaltered. Conclusions: Surprisingly, the contractile response to MLC-2 dephosphorylation is enhanced in failing hearts, despite the reduced level of basal MLC-2 phosphorylation. The enhanced response to MLC-2 dephosphorylation in failing myocytes might result from differences in basal phosphorylation of other thin and thick filament proteins between donor and failing hearts. Regulation of Ca2+-sensitivity via MLC-2 phosphorylation may be a potential compensatory mechanism to reverse the detrimental effects of increased Ca2+-sensitivity and impaired Ca2+-handling on diastolic function in human heart failure.

AB - Objective: Phosphorylation of the myosin light chain 2 (MLC-2) isoform expressed as a percentage of total MLC-2 was decreased in failing (21.1±2.0%) compared to donor (31.9±4.8%) hearts. To assess the functional implications of this change, we compared the effects of MLC-2 dephosphorylation on force development in failing and non-failing (donor) human hearts. Methods: Cooperative effects in isometric force and rate of force redevelopment (Ktr) were studied in single Triton-skinned human cardiomyocytes at various [Ca2+] before and after protein phosphatase-1 (PP-1) incubation. Results: Maximum force and Ktr values did not differ between failing and donor hearts, but Ca2+-sensitivity of force (pCa50) was significantly higher in failing myocardium (ΔpCa50=0.17). Ktr decreased with decreasing [Ca2+], although this decrease was less in failing than in donor hearts. Incubation of the myocytes with PP-1 (0.5 U/ml; 60 min) decreased pCa50 to a larger extent in failing (0.20 pCa units) than in donor cardiomyocytes (0.10 pCa units). A decrease in absolute Ktr values was found after PP-1 in failing and donor myocytes, while the shape of the Ktr-Ca2+ relationships remained unaltered. Conclusions: Surprisingly, the contractile response to MLC-2 dephosphorylation is enhanced in failing hearts, despite the reduced level of basal MLC-2 phosphorylation. The enhanced response to MLC-2 dephosphorylation in failing myocytes might result from differences in basal phosphorylation of other thin and thick filament proteins between donor and failing hearts. Regulation of Ca2+-sensitivity via MLC-2 phosphorylation may be a potential compensatory mechanism to reverse the detrimental effects of increased Ca2+-sensitivity and impaired Ca2+-handling on diastolic function in human heart failure.

KW - Cardiomyopathy

KW - Contractile apparatus

KW - Contractile function

KW - Myocytes

KW - Signal transduction

UR - http://www.scopus.com/inward/record.url?scp=12244249137&partnerID=8YFLogxK

U2 - 10.1016/S0008-6363(02)00662-4

DO - 10.1016/S0008-6363(02)00662-4

M3 - Article

VL - 57

SP - 505

EP - 514

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 2

ER -