Department of Clinical Medicine, Cardiovascular and Immunology Sciences, Federico II University School of Medicine, Via S. Pansini, 5, 80131 Naples, Italy.
Eur J Heart Fail. 2010 Dec;12(12):1290-6. doi: 10.1093/eurjhf/hfq102.
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.
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).
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.
几项研究表明，肌肉质量损失是心力衰竭（HF）的一个重要发病问题。Atrogin-1 是一种在心脏和骨骼肌组织中特异性表达的 F -box 蛋白，在肌肉消耗调节中起着关键作用。本研究旨在探讨 Atrogin-1 的表达及其在人类心力衰竭中的调节分子途径。
通过 Western blot 和实时 PCR 分析研究了心力衰竭患者（HF 组：n=10）或左心室功能正常的患者（对照组：n=9）的心脏组织。对患者左心室射血分数（LVEF）与 Atrogin1 或其调节因子叉头框 O3a（Foxo3a）心肌表达之间的线性回归分析，以检验蛋白表达与 LVEF 之间的相关性。Western blot 分析显示，HF 组心肌 Atrogin-1 的表达比对照组增加了 2.5 倍（P=0.007）。相应地，Atrogin-1mRNA 比对照组高 1.5 倍（P=0.003）。还测量了 Foxo3a 及其上游调节因子 AKT 的表达。Western blot 分析显示，HF 组 AKT 磷酸化减少了 2.56 倍，Foxo3a 增加了 3.32 倍，与对照组相比（P=0.002 和 P=0.001）。最后，线性回归显示 Foxo3a 或 Atrogin-1 表达与 LVEF 之间存在显著关系（R=0.976，P<0.0001 和 R=0.895，P=0.003）。
我们的结果表明，在人类心力衰竭中，AKT 的活性降低，Foxo3a 激活并诱导 Atrogin-1，从而导致有利于心肌丧失和左心室功能障碍的分子状态。
