压力过载
基因剔除小鼠
车站3
线粒体
内科学
内分泌学
肌肉肥大
心力衰竭
转录因子
生物
医学
磷酸化
细胞生物学
生物化学
基因
受体
心肌肥大
作者
Hongyu Qiu,Paulo Lizano,Lydie Laure,Xiangzhen Sui,Eman Rashed,Ji Yeon Park,Chull Hong,Shumin Gao,Eric Holle,Didier Morin,Sunil K. Dhar,Thomas E. Wagner,Alain Berdeaux,Bin Tian,Stephen F. Vatner,Christophe Depré
出处
期刊:Circulation
[Ovid Technologies (Wolters Kluwer)]
日期:2011-07-26
卷期号:124 (4): 406-415
被引量:101
标识
DOI:10.1161/circulationaha.110.013847
摘要
Cardiac overload, a major cause of heart failure, induces the expression of the heat shock protein H11 kinase/Hsp22 (Hsp22).To determine the specific function of Hsp22 in that context, a knockout mouse model of Hsp22 deletion was generated. Although comparable to wild-type mice in basal conditions, knockout mice exposed to pressure overload developed less hypertrophy and showed ventricular dilation, impaired contractile function, increased myocyte length and accumulation of interstitial collagen, faster transition into heart failure, and increased mortality. Microarrays revealed that hearts from knockout mice failed to transactivate genes regulated by the transcription factor STAT3. Accordingly, nuclear STAT3 tyrosine phosphorylation was decreased in knockout mice. Silencing and overexpression experiments in isolated neonatal rat cardiomyocytes showed that Hsp22 activates STAT3 via production of interleukin-6 by the transcription factor nuclear factor-κB. In addition to its transcriptional function, STAT3 translocates to the mitochondria where it increases oxidative phosphorylation. Both mitochondrial STAT3 translocation and respiration were also significantly decreased in knockout mice.This study found that Hsp22 represents a previously undescribed activator of both nuclear and mitochondrial functions of STAT3, and its deletion in the context of pressure overload in vivo accelerates the transition into heart failure and increases mortality.
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