Myocardial expression of FOXO3a-Atrogin-1 pathway in human heart failure.

Authors:
Gennaro Galasso
Gennaro Galasso
Federico II University
Italy
Federico Piscione
Federico Piscione
University of Salerno
Fisciano | Italy
Prof. Guido Iaccarino, MD, PhD
Prof. Guido Iaccarino, MD, PhD
Federico II University of Naples
Full Professor of Applied Medical Science and Technology
Cardiology
Napoli, Campania | Italy
Carlo Vosa
Carlo Vosa
University of Naples Federico II
Italy
Daniela Sorriento
Daniela Sorriento
Department of Clinical Medicine
Italy
Raffaele Piccolo
Raffaele Piccolo
Bern University Hospital
Bern | Switzerland
Antonio Rapacciuolo
Antonio Rapacciuolo
Federico II University
Italy

Eur J Heart Fail 2010 Dec;12(12):1290-6

Department of Clinical Medicine, Cardiovascular and Immunology Sciences, Federico II University School of Medicine, Via S. Pansini, 5, 80131 Naples, Italy.

Aims: 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.

Methods And 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).

Conclusion: 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.

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December 2010
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