2015年4月15日訊 /生物谷BIOON/ -- 近日，來自美國的華人科學家在國際學術期刊Diabetes在線發表了一項最新研究進展，他們發現AMPK抑制炎症過程主要是通過對STAT1信號途徑的抑制實現的，同時這一過程依賴於磷酸酶MKP-1蛋白水平的變化。
之前有研究發現AMPK能夠抑制炎症過程，但其具體機制仍不清楚。在該項研究中，研究人員對AMPK抑制血管炎症的具體分子機制進行了深入探討。他們在體外培養的人主動脈平滑肌細胞中，利用藥物或基因操作方法激活AMPK，發現AMPK的激活會抑制STAT1的活性，但抑制AMPK並不會出現相反的作用。
研究人員還發現不管是刪除AMPKα1還是AMPKα2都能導致STAT1的激活，增加促炎因子的表達，而通過siRNA或STAT1特異性抑制劑抑制STAT1活性則能消除因AMPK缺失導致的對炎症的促進效應。AMPK激活會抑制由STAT1激活因子如幹擾素-γ以及血管緊張素II誘導的促炎行為。
研究人員對機制進行探究發現AMPK激活會通過蛋白酶體依賴性途徑，調節可誘導型核磷酸酶MKP-1的降解，增加MKP-1蛋白水平，對MKP-1進行基因沉默會導致STAT1磷酸化增加。最終，研究人員發現給AMPKα2敲除小鼠的主動脈注入血管緊張素II會引起更加嚴重的炎症應答，而將STAT1特異性抑制劑以緩慢給藥的方式處理敲除小鼠則會抑制血管中的炎症應答反應。
總的來說，這篇文章發現了AMPK激活抑制了STAT1信號通路，同時通過上調MKP-1抑制了血管炎症，對於AMPK調節炎症過程進行了機制上的深入探討，具有一定意義。（生物谷Bioon.com）
AMP-activated Protein Kinase Suppresses Vascular Inflammation in vivo by Inhibiting Signal Transducer and Activator of Transcription-1
Chaoyong He1, Hongliang Li1, Benoit Viollet2,3,4, Ming-Hui Zou1? and Zhonglin Xie
Activation of AMP-activated protein kinase (AMPK) suppresses inflammation, but the underlying mechanisms remain poorly understood. This study was designed to characterize the molecular mechanisms by which AMPK suppresses vascular inflammation. In cultured human aortic smooth muscle cells, pharmacologic or genetic activation of AMPK inhibited the signal transducer and activator of transcription-1 (STAT1), while inhibition of AMPK had opposite effects. Deletion of either AMPKα1 or AMPKα2 resulted in activation of STAT1 and increases in proinflammatory mediators, both of which were attenuated by administration of STAT1 siRNA or fludarabine, a selective STAT1 inhibitor. Moreover, AMPK activation attenuated the proinflammatory actions induced by STAT1 activators such as interferon-γ and angiotensin II (AngII). Mechanistically, we found that AMPK activation increased, whereas AMPK inhibition decreased, the levels of mitogen-activated protein kinase phosphatase-1 (MKP-1), an inducible nuclear phosphatase, by regulating proteasome-dependent degradation of MKP-1. Gene silencing of MKP-1 increased STAT1 phosphorylation and prevented 5-Aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-reduced STAT1 phosphorylation. Finally, we found that infusion of AngII caused a more severe inflammatory response in AMPKα2 knockout mouse aortas, all of which were suppressed by chronic administration of fludarabine. We conclude that AMPK activation suppresses STAT1 signaling and inhibits vascular inflammation through the upregulation of MKP-1.