Overexpression of Myosin Phosphatase Reduces Ca2+ Sensitivity of Contraction and Impairs Cardiac Function

Hideo Mizutani; Ryuji Okamoto; Nobuyuki Moriki; Katsuhisa Konishi; Masaya Taniguchi; Satoshi Fujita; Kaoru Dohi; Katsuya Onishi; Noboru Suzuki; Shinji Satoh; Naoki Makino; Takeo Itoh; David J. Hartshorne; Masaaki Ito

doi:10.1253/circj.CJ-09-0462

Heart Failure

Overexpression of Myosin Phosphatase Reduces Ca²⁺ Sensitivity of Contraction and Impairs Cardiac Function

Hideo Mizutani, Ryuji Okamoto, Nobuyuki Moriki, Katsuhisa Konishi, Masaya Taniguchi, Satoshi Fujita, Kaoru Dohi, Katsuya Onishi, Noboru Suzuki, Shinji Satoh, Naoki Makino, Takeo Itoh, David J. Hartshorne, Masaaki Ito

Author information

Hideo Mizutani
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
Ryuji Okamoto
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
Nobuyuki Moriki
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
Katsuhisa Konishi
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
Masaya Taniguchi
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
Satoshi Fujita
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
Kaoru Dohi
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
Katsuya Onishi
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
Noboru Suzuki
Functional Genomics Institutes, Life Science Research Center, Mie University
Shinji Satoh
Department of Cardiology, National Hospital Organization Kyushu Medical Center
Naoki Makino
Division of Molecular and Clinical Gerontology, Medical Institute of Bioregulation, Kyushu university
Takeo Itoh
Department of Cellular and Molecular Pharmacology, Graduate School of Medical Sciences, Nagoya City University
David J. Hartshorne
Muscle Biology Group, University of Arizona
Masaaki Ito
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine

Keywords: Ca²⁺ sensitization, Myocardial contraction, Myosin light chain, Myosin phosphatase, Transgenic mouse

JOURNAL FREE ACCESS

2010 Volume 74 Issue 1 Pages 120-128

DOI https://doi.org/10.1253/circj.CJ-09-0462

View "Advance Publication" version (December 7, 2009).

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Abstract

Background: Phosphorylation of the regulatory light chain of myosin (MLC) has roles in cardiac function. In vitro, myosin phosphatase target subunit 2 (MYPT2) is a strongly suspected regulatory subunit of cardiac myosin phosphatase (MP), but there is no in-vivo evidence regarding the functions of MYPT2 in the heart. Methods and Results: Transgenic mice (Tg) overexpressing MYPT2 were generated using the α-MHC promoter. Tg hearts showed an increased expression of MYPT2 and concomitant increase of the endogenous catalytic subunit of type 1 phosphatase (PP1cδ), resulting in an increase of the MP holoenzyme. The level of phosphorylation of ventricular MLC was reduced. The pCa-tension relationship, using β-escin permeabilized fibers, revealed decreased Ca²⁺ sensitization of contraction in the Tg heart. LV enlargement with associated impairment of function was observed in the Tg heart and ultrastructural examination showed cardiomyocyte degeneration. Conclusions: Overexpression of MYPT2 and the increase in PP1cδ resulted in an increase of the MP holoenzyme and a decrease in the level of MLC phosphorylation. The latter induced Ca²⁺ desensitization of contraction and decreased LV contractility, resulting in LV enlargement. Thus, MYPT2 is truly the regulatory subunit of cardiac MP in-vivo and plays a significant role in modulating cardiac function. (Circ J 2010; 74: 120 - 128)

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