AMP-activated protein kinase is involved in endothelial NO synthase activation in response to shear stress.
OBJECTIVE
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).


RESULTS
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.


CONCLUSIONS
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.
Zhang
Yingjia
Y
Division of Biomedical Sciences, University of California, Riverside, CA 92521-0121, USA.
Lee
Tzong-Shyuan
TS
Kolb
Erik M
EM
Sun
Kai
K
Lu
Xiao
X
Sladek
Frances M
FM
Kassab
Ghassan S
GS
Garland
Theodore
T
Shyy
John Y-J
JY
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001011:Aorta / Q000201:enzymology; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011673:Pulsatile Flow; D013314:Stress, Mechanical
D009097:Multienzyme Complexes; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases