Flow activation of AMP-activated protein kinase in vascular endothelium leads to Krüppel-like factor 2 expression.
OBJECTIVE
Vascular endothelial cells (ECs) confer atheroprotection at locations of the arterial tree where pulsatile laminar flow (PS) exists with a high shear stress and a large net forward direction. We investigated whether the PS-induced expression of the transcription factor Krüppel-Like Factor 2 (KLF2) in cultured ECs and its expression in the mouse aorta is regulated by AMP-activated protein kinase (AMPK).


RESULTS
AMPK inhibition by Compound C or siRNA had a significant blocking effect on the PS-induced KLF2 expression. The induction of KLF2 by PS led to the increase in eNOS and the suppression of ET-1, which could be reversed by KLF2 siRNA. In addition, PS induced the phosphorylation of ERK5 and MEF2 which are necessary for the KLF2 expression. These mechanotransduction events were abrogated by the blockade of AMPK. Furthermore, the phosphorylation levels of ERK5 and MEF2, as well as the expression of KLF2, were significantly reduced in the aorta of AMPKalpha2 knockout mice when compared with wild-type control mice.


CONCLUSIONS
The flow-mediated AMPK activation is a newly defined KLF2 regulatory pathway in vascular endothelium that acts via ERK5/MEF2.
Young
Angela
A
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093-0412, USA.
Wu
Wei
W
Sun
Wei
W
Benjamin Larman
H
H
Larman
Harry B
HB
Wang
Nanping
N
Li
Yi-Shuan
YS
Shyy
John Y
JY
Chien
Shu
S
García-Cardeña
Guillermo
G
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001012:Aorta, Abdominal / Q000166:cytology; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D015151:Immunoblotting; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010766:Phosphorylation; D011336:Probability; D011673:Pulsatile Flow / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013314:Stress, Mechanical; D014162:Transfection; D015854:Up-Regulation
D018076:DNA, Complementary; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D055372:AMP-Activated Protein Kinases
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