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

The protein phosphatase 2A (PP2A) holoenzyme consists of a catalytic subuni t, C, and two regulatory subunits, A and B. The PP2A core enzyme is compose d of subunits A and C. Both the holoenzyme and the core enzyme are similarl y abundant in heart tissue. Transgenic mice were generated expressing high levels of a dominant negative mutant of the A subunit (A Delta 5) in the he art, 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 t hat the ratio of core enzyme to holoenzyme was increased in A Delta 5-expre ssing hearts. Importantly, already at day 1 after birth, A Delta 5-transgen ic mice had an increased heart weight-to-body weight ratio that persisted t hroughout life. Echocardiographic analysis of A Delta 5-transgenic hearts r evealed increased end-diastolic and end-systolic dimensions and decreased f ractional shortening. In addition, the thickness of the septum and of the l eft ventricular posterior wall was significantly reduced. On the basis of t hese findings, we consider the heart phenotype of A Delta 5-transgenic mice to be a form of dilated cardiomyopathy that frequently leads to premature death.