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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Ablation of Akt2 protects against lipopolysaccharide-induced cardiac dysfunction: Role of Akt ubiquitination E3 ligase TRAF6
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Ablation of Akt2 protects against lipopolysaccharide-induced cardiac dysfunction: Role of Akt ubiquitination E3 ligase TRAF6

机译：消融Akt2可防止脂多糖诱导的心脏功能障碍：Akt泛素化E3连接酶TRAF6的作用

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Lipopolysaccharide (LPS), an essential component of the outer membrane of Gram-negative bacteria, plays a pivotal role in myocardial anomalies in sepsis. Recent evidence has depicted a role of Akt in LPS-induced cardiac sequelae although little information is available with regard to the contribution of Akt isoforms in the endotoxin-induced cardiac dysfunction. This study examined the effect of Akt2 knockout on LPS-induced myocardial contractile dysfunction and the underlying mechanism(s) with a focus on TNF receptor-associated factor 6 (TRAF6). Echocardiographic properties and cardiomyocyte contractile function [peak shortening (PS), maximal velocity of shortening/relengthening, time-to-PS, time-to-90% relengthening] were examined in wild-type and Akt2 knockout mice following LPS challenge (4 mg/kg, 4 h). LPS challenge enlarged LV end systolic diameter, reduced fractional shortening and cardiomyocyte contractile capacity, prolonged TR_(90), promoted apoptosis, upregulated caspase-3/-12, ubiquitin, and the ubiquitination E3 ligase TRAF6 as well as decreased mitochondrial membrane potential without affecting the levels of TNF-alpha, toll-like receptor 4 and the mitochondrial protein ALDH2. Although Akt2 knockout failed to affect myocardial function, apoptosis, and ubiquitination, it significantly attenuated or mitigated LPS-induced changes in cardiac contractile and mitochondrial function, apoptosis and ubiquitination but not TRAF6. LPS facilitated ubiquitination, phosphorylation of Akt, GSL3beta and p38, the effect of which with the exception of p38 was ablated by Akt2 knockout. TRAF6 inhibitory peptide or RNA silencing significantly attenuated LPS-induced Akt2 ubiquitination, cardiac contractile anomalies and apoptosis. These data collectively suggested that TRAF6 may play a pivotal role in mediating LPS-induced cardiac injury via Akt2 ubiquitination.
机译：脂多糖（LPS）是革兰氏阴性细菌外膜的重要组成部分，在败血症的心肌异常中起关键作用。尽管Akt亚型在内毒素诱导的心脏功能障碍中的作用的信息很少，但最近的证据描述了Akt在LPS诱导的心脏后遗症中的作用。这项研究检查了Akt2基因敲除对LPS诱导的心肌收缩功能障碍的影响及其潜在机制，重点是TNF受体相关因子6（TRAF6）。在LPS攻击后，在野生型和Akt2敲除小鼠中检查了超声心动图特性和心肌收缩功能[峰值缩短（PS），最大缩短/延长速度，到PS的时间，到90％的时间延长的时间]（4 mg / kg，4小时）。 LPS挑战了扩大的LV末梢收缩直径，减小的缩短分数和心肌收缩能力，延长了TR_（90），促进了细胞凋亡，上调了caspase-3 / -12，泛素和E3连接酶TRAF6的泛素化，以及降低了线粒体膜电位，而没有影响TNF-α，toll​​样受体4和线粒体蛋白ALDH2的水平。尽管Akt2基因敲除未能影响心肌功能，细胞凋亡和泛素化，但它显着减弱或减轻了LPS诱导的心脏收缩和线粒体功能，细胞凋亡和泛素化的变化，但对TRAF6没有影响。 LPS促进了Akt，GSL3beta和p38的泛素化，磷酸化，除p38外，Akt2敲除消除了p38的作用。 TRAF6抑制性肽或RNA沉默显着减弱LPS诱导的Akt2泛素化，心脏收缩异常和细胞凋亡。这些数据共同表明，TRAF6可能在通过Akt2泛素化介导LPS诱导的心脏损伤中起关键作用。

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