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


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Abstract

AimsSeveral 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 resultsCardiac 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).ConclusionOur 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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