title: Myocardial expression of FOXO3a-Atrogin-1 pathway in human heart failure.
abstract: OBJECTIVE
  Several studies have shown that muscle mass loss is an important pathogenic issue in heart failure (HF). Atrogin-1 is a F-box protein selectively expressed in cardiac and skeletal muscle tissue, which plays a pivotal role in muscle wasting regulation. The aim of this study was to investigate the expression of Atrogin-1 and the molecular pathway involved in Atrogin-1 regulation in human HF.
  
  
  RESULTS
  Cardiac tissue from patients with HF (HF group: n=10) or with normal left ventricular function (control group: n=9) was studied by western blot and real time-PCR analysis. Linear regression analysis between patients left ventricular ejection fraction (LVEF) and Atrogin1 or its regulator Forkhead box O 3a (Foxo3a) myocardial expression was performed to test correlations between protein expression and LVEF. Western blot analysis revealed that the myocardial expression of Atrogin-1 in the HF group was 2.5-fold increased compared with controls (P=0.007). Accordingly, Atrogin-1 mRNA was 1.5 higher than in controls (P=0.003). The expression of Foxo3a and its up-stream regulator AKT were also measured. Western blot analysis demonstrated in the HF group a 2.56-fold reduction of AKT phosphorylation and a 3.32-fold increase of Foxo3a as compared with controls (P=0.002 and P=0.001, respectively). Finally, linear regression showed a significant relationship between Foxo3a or Atrogin-1 expression and LVEF (R=0.976, P<0.0001 and R=0.895, P=0.003, respectively).
  
  
  CONCLUSIONS
  Our results suggest that in human HF, the activity of AKT decreases, with activation of Foxo3a and induction of Atrogin-1, thereby leading to a molecular state that favours heart muscle loss and left ventricular dysfunction.
authors.affiliation: Department of Clinical Medicine, Cardiovascular and Immunology Sciences, Federico II University School of Medicine, Via S. Pansini, 5, 80131 Naples, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Galasso
authors.forename: Roberta
authors.initials: R
authors.lastname: De Rosa
authors.forename: Federico
authors.initials: F
authors.lastname: Piscione
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: Carlo
authors.initials: C
authors.lastname: Vosa
authors.forename: Daniela
authors.initials: D
authors.lastname: Sorriento
authors.forename: Raffaele
authors.initials: R
authors.lastname: Piccolo
authors.forename: Antonio
authors.initials: A
authors.lastname: Rapacciuolo
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Massimo
authors.initials: M
authors.lastname: Chiariello
mesh_terms: D000368:Aged; D015153:Blotting, Western; D016022:Case-Control Studies; D016001:Confidence Intervals; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D013223:Statistics as Topic; D016277:Ventricular Function, Left
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009124:Muscle Proteins; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases