title: Roles of cyclooxygenase-2 and phosphorylated Akt (Thr308) in cardiac hypertrophy regression mediated by left-ventricular unloading.
abstract: OBJECTIVE
  Cyclooxygenase-2 is associated with cardiac hypertrophy during chronic heart failure and is regulated through the PI3K/Akt pathway. Cyclooxygenase-2-induced cell growth through Akt phosphorylation was demonstrated in vitro. In chronic heart failure, left ventricular assist devices lead to hypertrophy regression and molecular changes. Therefore, the expression of cyclooxygenase-2, phosphorylated Akt (p-Akt), and p-Erk 1/2, as well as cardiac hypertrophy before and after left ventricular assist device insertion, was investigated.
  
  
  METHODS
  In myocardial tissue before and after left ventricular assist device insertion, the expression of cyclooxygenase-2, p-Akt (Thr308), p-Akt (Ser473), and p-Erk 1/2 was demonstrated by immunohistochemistry and quantified by morphometry. Colocalization of cyclooxygenase-2 and p-Akt (Thr308) was investigated by immuno-doublestaining.
  
  
  RESULTS
  A significant decrease of cyclooxygenase-2, p-Akt (Thr308), p-Akt (Ser473), and p-Erk 1/2 protein expression and hypertrophy regression was observed after left ventricular assist device insertion. A significant correlation between cyclooxygenase-2 and p-Akt (Thr308) expression, as well as between cyclooxygenase-2 expression and cardiomyocyte diameter, was observed before, but not after, left ventricular assist device insertion. Only cyclooxygenase-2-positive cardiomyocytes showed significant hypertrophy regression on unloading. Sarcoplasmic colocalization of cyclooxygenase-2 and p-Akt (Thr308) is present before left ventricular assist device insertion and is decreased after unloading, whereas the normal myocardium is completely devoid of it.
  
  
  CONCLUSIONS
  Left ventricular assist device treatment is associated with a significant decrease of cyclooxygenase-2, p-Akt (Thr308), p-Akt (Ser473), and p-Erk 1/2, and cardiac hypertrophy regression of cyclooxygenase-2-positive cardiomyocytes. The significant correlation and colocalization in cardiomyocytes of cyclooxygenase-2 and p-Akt (Thr308) before left ventricular assist device insertion suggests a cross-talk between the 2 molecules in the progression of cardiac hypertrophy, which is reversibly regulated by the left ventricular assist device.
authors.affiliation: Department of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Germany.
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.forename: Klaus Jürgen
authors.initials: KJ
authors.lastname: Schmitz
authors.forename: Jenci
authors.initials: J
authors.lastname: Palatty
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takeda
authors.forename: Nobuakira
authors.initials: N
authors.lastname: Takeda
authors.forename: Christian
authors.initials: C
authors.lastname: Vahlhaus
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Christof
authors.initials: C
authors.lastname: Schmid
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
authors.forename: Hideo Andreas
authors.initials: HA
authors.lastname: Baba
mesh_terms: D000293:Adolescent; D000328:Adult; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D048429:Cell Size; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3