Myocardial expression of FOXO3a-Atrogin-1 pathway in human heart failure
Myocardial expression of FOXO3a-Atrogin-1 pathway in human heart failure
复制标题
DOI：
10.1093/eurjhf/hfq102
复制
发表时间：
2010-12-01
影响因子：
18.2
通讯作者：
Chiariello, Massimo
中科院分区：
文献类型：
--
作者：
Galasso, Gennaro;De Rosa, Roberta;Chiariello, Massimo
一些研究表明，肌肉质量损失是心力衰竭（HF）的重要致病因素。Atrogin-1是一种选择性表达于心肌和骨骼肌组织的F-box蛋白，在肌肉萎缩调节中起着关键作用。为探讨Atrogin-1在人心力衰竭（HF）中的表达及其调控机制，采用Westernblot和真实的time-PCR技术，对10例HF患者和9例正常对照组的心脏组织进行了研究。采用直线回归法分析患者左室射血分数（LVEF）与Atrogin 1及其调节因子Forkhead box O 3a（Foxo 3a）心肌表达的相关性。Westernblot分析显示，与对照组相比，HF组心肌Atrogin-1的表达增加了2.5倍（P = 0.007）。相应地，Atrogin-1 mRNA比对照组高1.5（P = 0.003）。同时检测Foxo 3a及其上游调控因子AKT的表达。蛋白质印迹分析表明，与对照组相比，HF组AKT磷酸化减少2.56倍，Foxo 3a增加3.32倍（分别为P = 0.002和P = 0.001）。最后，线性回归显示Foxo 3a或Atrogin-1表达与LVEF之间存在显著相关性（R = 0.976，P < 0.0001和R = 0.895，P = 0.003）。我们的结果表明，在人HF中，AKT活性降低，Foxo 3a活化和Atrogin-1诱导，从而导致有利于心肌损失和左心室功能障碍的分子状态。
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.