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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1902.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Flow Activation of AMP-Activated Protein Kinase in Vascular Endothelium Leads to Krüppel-Like Factor 2 Expression

Angela Young; Wei Wu; Wei Sun; Harry B. Larman; Nanping Wang; Yi-Shuan Li; John Y. Shyy; Shu Chien; Guillermo García-Cardeña

From the Department of Bioengineering (A.Y., N.W., Y.-S.L., S.C.), University of California, San Diego, La Jolla; Biomedical Sciences (W.W., W.S., J.Y.S.), University of California, Riverside; and the Center for Excellence in Vascular Biology, Department of Pathology (H.B.L., G.G.-C.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Shu Chien, MD, PhD, Department of Bioengineering, UCSD, 9500, Gilman Drive, La Jolla, CA 92093-0412. E-mail shuchien{at}ucsd.edu

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).

Methods and 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 AMPK2 knockout mice when compared with wild-type control mice.

Conclusion— The flow-mediated AMPK activation is a newly defined KLF2 regulatory pathway in vascular endothelium that acts via ERK5/MEF2.

AMPK mediated the shear-induced phosphorylation of ERK5 and MEF2, which leads to the augmentation of KLF2 and the subsequent regulation of its downstream targets eNOS and ET-1 in cultured endothelial cells and the aortic wall.

Key Words: shear stress • endothelial cells • KLF2 • AMPK • eNOS

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