HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling
HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling
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DOI：
10.1152/ajpheart.00149.2014
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发表时间：
2014-07-15
影响因子：
4.8
通讯作者：
McKinsey, Timothy A.
中科院分区：
文献类型：
--
作者：
Demos-Davies, Kimberly M.;Ferguson, Bradley S.;McKinsey, Timothy A.
关于横纹肌中细胞质组蛋白去乙酰基酶HDAC6的功能知之甚少。在这里，我们讨论了HDAC6在多肽激素血管紧张素II(Ang II)诱导的心肌和骨骼肌重构中的作用，血管紧张素II在血压控制、心力衰竭和相关的骨骼肌萎缩中起着核心作用。与野生型(WT)小鼠相比，HDAC6基因缺失的小鼠在Ang II治疗后出现心肌肥大和纤维化。然而，WT小鼠在接受Ang II治疗后出现收缩功能障碍，而HDAC6基因缺失小鼠在接受Ang II治疗长达8wk时心功能保持不变。用小分子HDAC6抑制剂Tubasatin A治疗的WT小鼠可以模拟HDAC6缺失对心脏的保护作用，HDAC6基因缺失的小鼠在由横动脉收缩介导的压力超负荷状态下也表现出改善的左心功能。抑制HDAC6似乎部分地通过增强肌原纤维力产生的协同性来保护收缩功能。最后，我们发现HDAC6基因缺失的小鼠对慢性Ang-II信号介导的骨骼肌萎缩具有抵抗力。这些发现确定了HDAC6在横纹肌中的新作用，并表明HDAC6选择性抑制剂有可能用于治疗心力衰竭患者的心功能障碍和肌肉萎缩。
Little is known about the function of the cytoplasmic histone deacetylase HDAC6 in striated muscle. Here, we addressed the role of HDAC6 in cardiac and skeletal muscle remodeling induced by the peptide hormone angiotensin II (ANG II), which plays a central role in blood pressure control, heart failure, and associated skeletal muscle wasting. Comparable with wild-type (WT) mice, HDAC6 null mice developed cardiac hypertrophy and fibrosis in response to ANG II. However, whereas WT mice developed systolic dysfunction upon treatment with ANG II, cardiac function was maintained in HDAC6 null mice treated with ANG II for up to 8 wk. The cardioprotective effect of HDAC6 deletion was mimicked in WT mice treated with the small molecule HDAC6 inhibitor tubastatin A. HDAC6 null mice also exhibited improved left ventricular function in the setting of pressure overload mediated by transverse aortic constriction. HDAC6 inhibition appeared to preserve systolic function, in part, by enhancing cooperativity of myofibrillar force generation. Finally, we show that HDAC6 null mice are resistant to skeletal muscle wasting mediated by chronic ANG-II signaling. These findings define novel roles for HDAC6 in striated muscle and suggest potential for HDAC6-selective inhibitors for the treatment of cardiac dysfunction and muscle wasting in patients with heart failure.