Overexpression of myosin phosphatase reduces Ca(2+) sensitivity of contraction and impairs cardiac function.
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.


RESULTS
Transgenic mice (Tg) overexpressing MYPT2 were generated using the alpha-MHC promoter. Tg hearts showed an increased expression of MYPT2 and concomitant increase of the endogenous catalytic subunit of type 1 phosphatase (PP1cdelta), resulting in an increase of the MP holoenzyme. The level of phosphorylation of ventricular MLC was reduced. The pCa-tension relationship, using beta-escin permeabilized fibers, revealed decreased Ca(2+) 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 PP1cdelta resulted in an increase of the MP holoenzyme and a decrease in the level of MLC phosphorylation. The latter induced Ca(2+) 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).
Mizutani
Hideo
H
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Japan.
Okamoto
Ryuji
R
Moriki
Nobuyuki
N
Konishi
Katsuhisa
K
Taniguchi
Masaya
M
Fujita
Satoshi
S
Dohi
Kaoru
K
Onishi
Katsuya
K
Suzuki
Noboru
N
Satoh
Shinji
S
Makino
Naoki
N
Itoh
Takeo
T
Hartshorne
David J
DJ
Ito
Masaaki
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018994:Myosin Light Chains / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism
D018994:Myosin Light Chains; D021122:Protein Subunits; D043263:Myosin-Light-Chain Phosphatase; D002118:Calcium