Myosin light chain phosphorylation is critical for adaptation to cardiac stress

Sonisha A. Warren, Laura E. Briggs, Huadong Zeng, Joyce Chuang, Eileen I. Chang, Ryota Terada, Moyi Li, Maurice S. Swanson, Stewart H. Lecker, Monte Willis, Francis G. Spinale, Julie Maupin-Furlowe, Julie R. McMullen, Richard L. Moss, Hideko Kasahara

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Background : Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac myosin light-chain kinase (cMLCK), yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined. Methods and Results: We found that pressure overload induced by transaortic constriction in wild-type mice reduced phosphorylated MLC2v levels by ≈40% and cMLCK levels by ≈85%. To examine how a reduction in cMLCK and the corresponding reduction in phosphorylated MLC2v affect function, we generated Mylk3 gene-targeted mice and transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure overload led to severe heart failure in cMLCK knockout mice but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems. Conclusions: Our results suggest the novel idea that accelerated cMLCK protein turnover by the ubiquitin-proteasome system underlies the transition from compensated hypertrophy to decompensated heart failure as a result of reduced phosphorylation of MLC2v.

Original languageEnglish (US)
Pages (from-to)2575-2588
Number of pages14
JournalCirculation
Volume126
Issue number22
DOIs
StatePublished - Oct 31 2012
Externally publishedYes

Fingerprint

Cardiac Myosins
Myosin Light Chains
Myosin-Light-Chain Kinase
Phosphorylation
Heart Failure
Proteasome Endopeptidase Complex
Myosins
Ubiquitin
Cardiac Myocytes
Pressure
Proteins
Cardiomegaly
Constriction
Knockout Mice
Hypertrophy
Transgenic Mice
Proteolysis
Actins

Keywords

  • heart failure
  • mice
  • myocardial contraction
  • myosin light chains
  • phosphorylation
  • transgenic

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Warren, S. A., Briggs, L. E., Zeng, H., Chuang, J., Chang, E. I., Terada, R., ... Kasahara, H. (2012). Myosin light chain phosphorylation is critical for adaptation to cardiac stress. Circulation, 126(22), 2575-2588. https://doi.org/10.1161/CIRCULATIONAHA.112.116202

Myosin light chain phosphorylation is critical for adaptation to cardiac stress. / Warren, Sonisha A.; Briggs, Laura E.; Zeng, Huadong; Chuang, Joyce; Chang, Eileen I.; Terada, Ryota; Li, Moyi; Swanson, Maurice S.; Lecker, Stewart H.; Willis, Monte; Spinale, Francis G.; Maupin-Furlowe, Julie; McMullen, Julie R.; Moss, Richard L.; Kasahara, Hideko.

In: Circulation, Vol. 126, No. 22, 31.10.2012, p. 2575-2588.

Research output: Contribution to journalArticle

Warren, SA, Briggs, LE, Zeng, H, Chuang, J, Chang, EI, Terada, R, Li, M, Swanson, MS, Lecker, SH, Willis, M, Spinale, FG, Maupin-Furlowe, J, McMullen, JR, Moss, RL & Kasahara, H 2012, 'Myosin light chain phosphorylation is critical for adaptation to cardiac stress', Circulation, vol. 126, no. 22, pp. 2575-2588. https://doi.org/10.1161/CIRCULATIONAHA.112.116202
Warren SA, Briggs LE, Zeng H, Chuang J, Chang EI, Terada R et al. Myosin light chain phosphorylation is critical for adaptation to cardiac stress. Circulation. 2012 Oct 31;126(22):2575-2588. https://doi.org/10.1161/CIRCULATIONAHA.112.116202
Warren, Sonisha A. ; Briggs, Laura E. ; Zeng, Huadong ; Chuang, Joyce ; Chang, Eileen I. ; Terada, Ryota ; Li, Moyi ; Swanson, Maurice S. ; Lecker, Stewart H. ; Willis, Monte ; Spinale, Francis G. ; Maupin-Furlowe, Julie ; McMullen, Julie R. ; Moss, Richard L. ; Kasahara, Hideko. / Myosin light chain phosphorylation is critical for adaptation to cardiac stress. In: Circulation. 2012 ; Vol. 126, No. 22. pp. 2575-2588.
@article{2eae7f46d9ec4492887f49a5cef220ac,
title = "Myosin light chain phosphorylation is critical for adaptation to cardiac stress",
abstract = "Background : Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac myosin light-chain kinase (cMLCK), yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined. Methods and Results: We found that pressure overload induced by transaortic constriction in wild-type mice reduced phosphorylated MLC2v levels by ≈40{\%} and cMLCK levels by ≈85{\%}. To examine how a reduction in cMLCK and the corresponding reduction in phosphorylated MLC2v affect function, we generated Mylk3 gene-targeted mice and transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure overload led to severe heart failure in cMLCK knockout mice but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems. Conclusions: Our results suggest the novel idea that accelerated cMLCK protein turnover by the ubiquitin-proteasome system underlies the transition from compensated hypertrophy to decompensated heart failure as a result of reduced phosphorylation of MLC2v.",
keywords = "heart failure, mice, myocardial contraction, myosin light chains, phosphorylation, transgenic",
author = "Warren, {Sonisha A.} and Briggs, {Laura E.} and Huadong Zeng and Joyce Chuang and Chang, {Eileen I.} and Ryota Terada and Moyi Li and Swanson, {Maurice S.} and Lecker, {Stewart H.} and Monte Willis and Spinale, {Francis G.} and Julie Maupin-Furlowe and McMullen, {Julie R.} and Moss, {Richard L.} and Hideko Kasahara",
year = "2012",
month = "10",
day = "31",
doi = "10.1161/CIRCULATIONAHA.112.116202",
language = "English (US)",
volume = "126",
pages = "2575--2588",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "22",

}

TY - JOUR

T1 - Myosin light chain phosphorylation is critical for adaptation to cardiac stress

AU - Warren, Sonisha A.

AU - Briggs, Laura E.

AU - Zeng, Huadong

AU - Chuang, Joyce

AU - Chang, Eileen I.

AU - Terada, Ryota

AU - Li, Moyi

AU - Swanson, Maurice S.

AU - Lecker, Stewart H.

AU - Willis, Monte

AU - Spinale, Francis G.

AU - Maupin-Furlowe, Julie

AU - McMullen, Julie R.

AU - Moss, Richard L.

AU - Kasahara, Hideko

PY - 2012/10/31

Y1 - 2012/10/31

N2 - Background : Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac myosin light-chain kinase (cMLCK), yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined. Methods and Results: We found that pressure overload induced by transaortic constriction in wild-type mice reduced phosphorylated MLC2v levels by ≈40% and cMLCK levels by ≈85%. To examine how a reduction in cMLCK and the corresponding reduction in phosphorylated MLC2v affect function, we generated Mylk3 gene-targeted mice and transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure overload led to severe heart failure in cMLCK knockout mice but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems. Conclusions: Our results suggest the novel idea that accelerated cMLCK protein turnover by the ubiquitin-proteasome system underlies the transition from compensated hypertrophy to decompensated heart failure as a result of reduced phosphorylation of MLC2v.

AB - Background : Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac myosin light-chain kinase (cMLCK), yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined. Methods and Results: We found that pressure overload induced by transaortic constriction in wild-type mice reduced phosphorylated MLC2v levels by ≈40% and cMLCK levels by ≈85%. To examine how a reduction in cMLCK and the corresponding reduction in phosphorylated MLC2v affect function, we generated Mylk3 gene-targeted mice and transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure overload led to severe heart failure in cMLCK knockout mice but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems. Conclusions: Our results suggest the novel idea that accelerated cMLCK protein turnover by the ubiquitin-proteasome system underlies the transition from compensated hypertrophy to decompensated heart failure as a result of reduced phosphorylation of MLC2v.

KW - heart failure

KW - mice

KW - myocardial contraction

KW - myosin light chains

KW - phosphorylation

KW - transgenic

UR - http://www.scopus.com/inward/record.url?scp=84870255293&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870255293&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.112.116202

DO - 10.1161/CIRCULATIONAHA.112.116202

M3 - Article

VL - 126

SP - 2575

EP - 2588

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 22

ER -