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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.

journal_name

Circulation

journal_title

Circulation

authors

Warren SA,Briggs LE,Zeng H,Chuang J,Chang EI,Terada R,Li M,Swanson MS,Lecker SH,Willis MS,Spinale FG,Maupin-Furlowe J,McMullen JR,Moss RL,Kasahara H

doi

10.1161/CIRCULATIONAHA.112.116202

subject

Has Abstract

pub_date

2012-11-27 00:00:00

pages

2575-88

issue

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.112.116202

journal_volume

126

pub_type

杂志文章

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Myosin light chain phosphorylation is critical for adaptation to cardiac stress.