Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy.
Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy.
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IKKvarepsilon 抑制剂是病理性心脏肥大的重要负调节因子。
DOI：
10.1038/ncomms11432
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发表时间：
2016-06-01
影响因子：
16.6
通讯作者：
Li H
中科院分区：
文献类型：
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作者：
Deng KQ;Wang A;Ji YX;Zhang XJ;Fang J;Zhang Y;Zhang P;Jiang X;Gao L;Zhu XY;Zhao Y;Gao L;Yang Q;Zhu XH;Wei X;Pu J;Li H
虽然病理性心脏肥大是世界范围内发病率和死亡率的主要原因，但我们对这种疾病的分子机制的理解仍然很差。在这里，我们证明了IKK抑制剂（SIKE），干扰素通路的负调节剂，以TANK结合激酶1（TBK 1）/AKT依赖的方式减弱啮齿动物和非人灵长类动物的病理性心脏肥大。Sike缺陷小鼠发生心脏肥大和心力衰竭，而Sike过表达转基因（Sike-TG）小鼠免受肥大刺激。在机制上，SIKE直接与TBK 1相互作用以抑制TBK 1-AKT信号通路，从而实现其抗肥大作用。在大鼠和猴中进一步验证了SIKE对心脏重塑的抑制。总的来说，这些研究结果表明，由于其对TBK 1/AKT轴的抑制性调节，SIKE在多种动物物种中是心脏重塑的负调节剂，这表明SIKE可能代表用于治疗心脏肥大和心力衰竭的治疗靶点。 识别导致病理性心脏肥大的途径具有巨大的治疗潜力。在这里，作者发现了一个这样的途径，并表明干扰素信号传导抑制剂SIKE通过与TBK 1相互作用并调节啮齿动物和猴子中的TBK 1/AKT信号传导来预防病理性而非生理性心脏肥大。
Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure. Identifying pathways that cause pathological cardiac hypertrophy holds great therapeutic potential. Here the authors discover one such pathway and show that SIKE, an inhibitor of interferon signalling, prevents pathological but not physiological cardiac hypertrophy by interacting with TBK1 and modulating the TBK1/AKT signalling in rodents and monkeys.