Overexpression of Myosin Phosphatase Reduces Ca2+ Sensitivity of Contraction and Impairs Cardiac Function
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概要
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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.
著者
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Dohi Kaoru
Department Of Cardiology And Nephrology Mie University Graduate School Of Medicine
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Itoh Takeo
Department Of Cellular And Molecular Pharmacology Graduate School Of Medical Sciences Nagoya City Un
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Makino Naoki
Division Of Molecular And Clinical Gerontology Department Of Molecular And Cellular Biology Medical
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MORIKI Nobuyuki
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
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KONISHI Katsuhisa
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
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Mizutani Hideo
Department Of Cardiology And Nephrology Mie University Graduate School Of Medicine
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Moriki Nobuyuki
Department Of Cardiology And Nephrology Mie University Graduate School Of Medicine
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Okamoto Ryuji
Department Of Cardiology And Nephrology Mie University Graduate School Of Medicine
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Hartshorne David
Muscle Biology Group College Of Agr. Univ. Of Arizona
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Taniguchi Masaya
Department Of Cardiology And Nephrology Mie University Graduate School Of Medicine
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Konishi Katsuhisa
Department Of Cardiology And Nephrology Mie University Graduate School Of Medicine
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Suzuki Noboru
Functional Genomics Institutes Life Science Research Center Mie University
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Fujita Satoshi
Department Of Anesthesiology School Of Medicine Sapporo Medical University
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Ito Masaaki
Department Of Agricultural Chemistry Yamagata University
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Satoh Shinji
Department Of Bioclimatology And Medicine Medical Institute Of Bioregulation Kyushu University
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Satoh Shinji
Department of Cardiology, National Hospital Organization Kyushu Medical Center
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Onishi Katsuya
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
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Dohi Kaoru
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
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