Alpha B-crystallin suppresses pressure overload cardiac hypertrophy.
Alpha B-crystallin suppresses pressure overload cardiac hypertrophy.
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DOI：
10.1161/circresaha.108.180117
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发表时间：
2008-12-05
影响因子：
20.1
通讯作者：
Wang, Xuejun
中科院分区：
文献类型：
--
作者：
Kumarapeli, Asangi R. K.;Su, Huabo;Huang, Wei;Tang, Mingxin;Zheng, Hanqiao;Horak, Kathleen M.;Li, Manxiang;Wang, Xuejun
关键词：
αB-晶体蛋白(CryAB)是心肌细胞中成分最丰富的小分子热休克蛋白。功能获得和功能丧失研究表明，CryAB对心肌缺血/再灌注损伤具有保护作用。然而，CryAB或任何HSPs在机械超负荷心脏反应中的作用尚不清楚。这项研究解决了这个问题。非转基因(NTG)小鼠和心肌细胞限制性转基因CryAB(TG)过表达或CryAB/HSPB2基因(KO)胚系消融的小鼠接受横动脉缩窄(TAC)或假手术。两周后，通过胎儿基因表达谱、心功能分析和形态计量学分析心脏反应。3个假手术组之间的比较显示，CryAB的过度表达是良性的，而KO是有害的，10周龄时表现为心肌肥大和功能障碍。与NTG小鼠相比，TG组小鼠心脏NFAT反式激活显著减少，对TAC的肥大反应减弱，但心功能无明显变化，而KO小鼠心肌和骨骼肌NFAT反式激活显著增加，并在TAC后2周出现心功能不全。在培养的新生大鼠心肌细胞中过表达CryAB可显著减弱肾上腺素能刺激诱导的NFAT反式激活和肥大生长。我们的结论是，CryAB可能通过减弱NFAT信号来抑制心脏肥厚反应，并且CryAB和/或HSPB2对于正常的心功能是必不可少的。
αB-Crystallin (CryAB) is the most abundant small heat shock protein (HSP) constitutively expressed in cardiomyocytes. Gain- and loss-of-function studies demonstrated that CryAB can protect against myocardial ischemia/reperfusion injury. However, the role of CryAB or any HSPs in cardiac responses to mechanical overload is unknown. This study addresses this issue. Non-transgenic (NTG) mice and mice with cardiomyocyte-restricted transgenic overexpression of CryAB (TG) or with germ-line ablation of the CryAB/HSPB2 genes (KO) were subjected to transverse aortic constriction (TAC) or sham surgery. Two weeks later, cardiac responses were analyzed by fetal gene expression profiling, cardiac function analyses, and morphometry. Comparison among the 3 sham surgery groups reveals that CryAB overexpression is benign whereas the KO is detrimental to the heart as reflected by cardiac hypertrophy and malfunction at 10 weeks of age. Compared to NTG mice, TG mouse hearts showed significantly reduced NFAT transactivation and attenuated cardiac hypertrophic responses to TAC but unchanged cardiac function, whereas NFAT transactivation was significantly increased in cardiac and skeletal muscle of the KO mice at baseline and they developed cardiac insufficiency at 2 weeks after TAC. CryAB overexpression in cultured neonatal rat cardiomyocytes significantly attenuated adrenergic stimulation-induced NFAT transactivation and hypertrophic growth. We conclude that CryAB suppresses cardiac hypertrophic responses likely through attenuating NFAT signaling and CryAB and/or HSPB2 are essential for normal cardiac function.