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Circ J. 2010 Jan;74(1):120-8. Epub 2009 Dec 7.

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

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  • 1Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Japan.

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 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).

PMID:
19966500
[PubMed - indexed for MEDLINE]
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