AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol 279: H1307-H1318, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 3, H1307-H1318, September 2000

Dilated cardiomyopathy in transgenic mice expressing a mutant A subunit of protein phosphatase 2A

Neil Brewis1,*, Kim Ohst1,*, Katherine Fields1, Antonio Rapacciuolo3, Danny Chou1, Colin Bloor1, Wolfgang Dillmann2, Howard Rockman3, and Gernot Walter1

1 Department of Pathology and 2 Department of Medicine, University of California San Diego, La Jolla, California 92093; and 3 Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

The protein phosphatase 2A (PP2A) holoenzyme consists of a catalytic subunit, C, and two regulatory subunits, A and B. The PP2A core enzyme is composed of subunits A and C. Both the holoenzyme and the core enzyme are similarly abundant in heart tissue. Transgenic mice were generated expressing high levels of a dominant negative mutant of the A subunit (ADelta 5) in the heart, skeletal muscle, and smooth muscle that competes with the endogenous A subunit for binding the C subunit but does not bind B subunits. We found that the ratio of core enzyme to holoenzyme was increased in ADelta 5-expressing hearts. Importantly, already at day 1 after birth, ADelta 5-transgenic mice had an increased heart weight-to-body weight ratio that persisted throughout life. Echocardiographic analysis of ADelta 5-transgenic hearts revealed increased end-diastolic and end-systolic dimensions and decreased fractional shortening. In addition, the thickness of the septum and of the left ventricular posterior wall was significantly reduced. On the basis of these findings, we consider the heart phenotype of ADelta 5-transgenic mice to be a form of dilated cardiomyopathy that frequently leads to premature death.

protein phosphatase 2A holoenzyme; protein phosphatase 2A core enzyme; heart weight-to-body weight ratio; muscle-specific gene expression

* Authors have contributed equally to this paper.




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