title: Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy.
abstract: 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.
authors.affiliation: Gazes Cardiac Research Institute, Cardiology Division, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29403, USA.
authors.forename: Guangmao
authors.initials: G
authors.lastname: Cheng
authors.forename: Masaru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Anandakumar
authors.initials: A
authors.lastname: Shunmugavel
authors.forename: J Grace
authors.initials: JG
authors.lastname: Wallenborn
authors.forename: Anna A
authors.initials: AA
authors.lastname: DePaoli-Roach
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gergs
authors.forename: Joachim
authors.initials: J
authors.lastname: Neumann
authors.forename: Dhandapani
authors.initials: D
authors.lastname: Kuppuswamy
authors.forename: Donald R
authors.initials: DR
authors.lastname: Menick
authors.forename: George
authors.initials: G
authors.lastname: Cooper
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002415:Cats; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D054648:Protein Phosphatase 2