Increased activity of Ser/Thr
protein phosphatases types 1 (PP1) and 2A (PP2A) during maladaptive
cardiac hypertrophy contributes to cardiac dysfunction and eventual failure, partly through effects on
calcium metabolism. A second maladaptive feature of pressure overload
cardiac hypertrophy that instead leads to
heart failure by interfering with cardiac contraction and intracellular transport is a dense microtubule network stabilized by decoration with
microtubule-associated protein 4 (
MAP4). In an earlier study we showed that the major determinant of MAP4-microtubule affinity, and thus microtubule network density and stability, is site-specific
MAP4 dephosphorylation at Ser-924 and to a lesser extent at Ser-1056; this was found to be prominent in hypertrophied myocardium. Therefore, in seeking the etiology of this
MAP4 dephosphorylation, we looked here at PP2A and PP1, as well as the upstream
p21-activated kinase 1, in maladaptive pressure overload
cardiac hypertrophy. The activity of each was increased persistently during maladaptive
hypertrophy, and overexpression of PP2A or PP1 in normal hearts reproduced both the microtubule network phenotype and the dephosphorylation of
MAP4 Ser-924 and Ser-1056 seen in
hypertrophy. Given the major microtubule-based abnormalities of contractile and transport function in maladaptive
hypertrophy, these findings constitute a second important mechanism for
phosphatase-dependent pathology in the hypertrophied and failing heart.