Zhang Yingjia, Lee Tzong-Shyuan, Kolb Erik M, Sun Kai, Lu Xiao, Sladek Frances M, Kassab Ghassan S, Garland Theodore, Shyy John Y-J
Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121, USA.
Arterioscler Thromb Vasc Biol. 2006 Jun;26(6):1281-7. doi: 10.1161/01.ATV.0000221230.08596.98. Epub 2006 Apr 6.
The regulation of AMP-activated protein kinase (AMPK) is implicated in vascular biology because AMPK can phosphorylate endothelial NO synthase (eNOS). In this study, we investigate the regulation of the AMPK-eNOS pathway in vascular endothelial cells (ECs) by shear stress and the activation of aortic AMPK in a mouse model with a high level of voluntary running (High-Runner).
By using flow channels with cultured ECs, AMPK Thr172 phosphorylation was increased with changes of flow rate or pulsatility. The activity of LKB1, the upstream kinase of AMPK, and the phosphorylation of eNOS at Ser1179 were concomitant with AMPK activation responding to changes in flow rate or pulsatility. The blockage of AMPK by a dominant-negative mutant of AMPK inhibited shear stress-induced eNOS Ser1179 phosphorylation and NO production. Furthermore, aortic AMPK activity and level of eNOS phosphorylation were significantly elevated in the aortas of High-Runner mice.
Our results suggest that shear stress activates AMPK in ECs, which contributes to elevated eNOS activity and subsequent NO production. Hence, AMPK, in addition to serving as an energy sensor, also plays an important role in regulating vascular tone.
AMP 激活的蛋白激酶（AMPK）的调节与血管生物学相关，因为 AMPK 可磷酸化内皮型一氧化氮合酶（eNOS）。在本研究中，我们研究了剪切应力对血管内皮细胞（ECs）中 AMPK-eNOS 途径的调节以及在高水平自主运动小鼠模型（高运动组）中主动脉 AMPK 的激活情况。
通过使用培养有 ECs 的流动通道，随着流速或搏动性的变化，AMPK Thr172 磷酸化增加。AMPK 的上游激酶 LKB1 的活性以及 eNOS 在 Ser1179 位点的磷酸化与 AMPK 对流速或搏动性变化的激活同时发生。用 AMPK 的显性负性突变体阻断 AMPK 可抑制剪切应力诱导的 eNOS Ser1179 磷酸化和一氧化氮生成。此外，高运动组小鼠主动脉中 AMPK 活性和 eNOS 磷酸化水平显著升高。
我们的结果表明，剪切应力激活 ECs 中的 AMPK，这有助于提高 eNOS 活性并随后生成一氧化氮。因此，AMPK 除了作为能量传感器外，在调节血管张力方面也起着重要作用。
