title: Physiological activation of Akt by PHLPP1 deletion protects against pathological hypertrophy.
abstract: OBJECTIVE
  To examine the role of physiological Akt signalling in pathological hypertrophy through analysis of PHLPP1 (PH domain leucine-rich repeat protein phosphatase) knock-out (KO) mice.
  
  
  RESULTS
  To investigate the in vivo requirement for 'physiological' control of Akt activation in cardiac growth, we examined the effect of deleting the Akt phosphatase, PHLPP, on the induction of cardiac hypertrophy. Basal Akt phosphorylation increased nearly two-fold in the cardiomyocytes from PHLPP1 KO mice and physiological hypertrophy induced by swimming exercise was accentuated as assessed by increased heart size and myocyte cell area. In contrast, the development of pathophysiological hypertrophy induced by pressure overload and assessed by increases in heart size, myocyte cell area, and hypertrophic gene expression was attenuated. This attenuation coincided with decreased fibrosis and cell death in the KO mice. Cast moulding revealed increased capillary density basally in the KO hearts, which was further elevated relative to wild-type mouse hearts in response to pressure overload. In vitro studies with isolated myocytes in co-culture also demonstrated that PHLPP1 deletion in cardiomyocytes can enhance endothelial tube formation. Expression of the pro-angiogenic factor VEGF was also elevated basally and accentuated in response to transverse aortic constriction in hearts from KO mice.
  
  
  CONCLUSIONS
  Our data suggest that enhancing Akt activity by inhibiting its PHLPP1-mediated dephosphorylation promotes processes associated with physiological hypertrophy that may be beneficial in attenuating the development of pathological hypertrophy.
authors.affiliation: Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Moc
authors.affiliation: Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
authors.forename: Gino P
authors.initials: GP
authors.lastname: Chesini
authors.affiliation: Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Zambrano
authors.affiliation: Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Barlow
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Åsa B
authors.initials: ÅB
authors.lastname: Gustafsson
authors.affiliation: Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA npurcell@ucsd.edu.
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Purcell
mesh_terms: D000818:Animals; D006321:Heart / Q000503:physiopathology; D006984:Hypertrophy / Q000235:genetics* / Q000378:metabolism; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; C519282:PHLPP1 protein, mouse; D010749:Phosphoprotein Phosphatases
keywords: Akt; Hypertrophy; Mouse model; PH domain leucine-rich repeat protein phosphatase; PHLPP