Mechanism and Role of High Density Lipoprotein-induced Activation of AMP-activated Protein Kinase in Endothelial Cells
Mechanism and Role of High Density Lipoprotein-induced Activation of AMP-activated Protein Kinase in Endothelial Cells
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DOI：
10.1074/jbc.m109.043869
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发表时间：
2010-02-12
影响因子：
4.8
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
--
作者：
Kimura, Takao;Tomura, Hideaki;Okajima, Fumikazu
研究高密度脂蛋白(HDL)激活AMP活化蛋白激酶(AMPK)的上游信号通路以及AMPK在高密度脂蛋白(HDL)诱导的抗动脉粥样硬化作用中的作用。使用遗传学和药理学工具的实验表明，高密度脂蛋白诱导的AMPK的激活依赖于神经鞘氨醇1-磷酸受体和清道夫受体BI型，通过钙/钙调蛋白依赖的蛋白激酶，以及对于清道夫受体BI型系统，另外，在人脐静脉内皮细胞中，丝氨酸-苏氨酸激酶LKB1。高密度脂蛋白诱导的Akt和内皮一氧化氮合酶的激活、迁移的刺激以及单核细胞黏附和黏附分子表达的抑制依赖于AMPK的激活。体内、外实验均证实AMPK对小鼠主动脉内皮细胞黏附分子表达及单核细胞黏附的抑制作用。另一方面，AMPK基因敲除对ERK的刺激和增殖几乎没有影响，但被N17Ras完全抑制，而显性负性RAS对AMPK的激活无效。综上所述，双高密度脂蛋白受体系统通过钙/钙调蛋白依赖的蛋白激酶和/或LKB1来不同地调节AMPK的活性。一些高密度脂蛋白诱导的抗动脉粥样硬化作用受AMPK调节，但与增殖相关的作用受RAS而不是AMPK调节。
The upstream signaling pathway leading to the activation of AMP-activated protein kinase (AMPK) by high density lipoprotein (HDL) and the role of AMPK in HDL-induced antiatherogenic actions were investigated. Experiments using genetic and pharmacological tools showed that HDL-induced activation of AMPK is dependent on both sphingosine 1-phosphate receptors and scavenger receptor class B type I through calcium/calmodulin dependent protein kinase kinase and, for scavenger receptor class B type I system, additionally serine-threonine kinase LKB1 in human umbilical vein endothelial cells. HDL-induced activation of Akt and endothelial NO synthase, stimulation of migration, and inhibition of monocyte adhesion and adhesion molecule expression were dependent on AMPK activation. The inhibitory role of AMPK in the adhesion molecule expression and monocyte adhesion on endothelium of mouse aorta was confirmed in vivo and ex vivo. On the other hand, stimulation of ERK and proliferation were hardly affected by AMPK knockdown but completely inhibited by an N17Ras, whereas the dominant-negative Ras was ineffective for AMPK activation. In conclusion, dual HDL receptor systems differentially regulate AMPK activity through calcium/calmodulin-dependent protein kinase kinase and/or LKB1. Several HDL-induced antiatherogenic actions are regulated by AMPK, but proliferation-related actions are regulated by Ras rather than AMPK.