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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2255.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Inhibition of Tumor Necrosis Factor –Stimulated Monocyte Adhesion to Human Aortic Endothelial Cells by AMP-Activated Protein Kinase

Marie-Ann Ewart; Christine F. Kohlhaas; Ian P. Salt

From the Henry Wellcome Laboratory for Cell Biology, Division of Molecular and Cellular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, UK.

Correspondence to Ian Salt, Henry Wellcome Laboratory for Cell Biology, Division of Molecular and Cellular Biology, Faculty of Biomedical and Life Sciences, Davidson Building, University of Glasgow, Glasgow G12 8QQ, UK. E-mail i.salt{at}bio.gla.ac.uk

Objective— Proatherosclerotic adhesion of leukocytes to the endothelium is attenuated by NO. As AMP-activated protein kinase (AMPK) regulates endothelial NO synthesis, we investigated the modulation of adhesion to cultured human aortic endothelial cells (HAECs) by AMPK.

Methods and Results— HAECs incubated with the AMPK activator, AICAR, or expressing constitutively active AMPK demonstrated reduced TNF-stimulated adhesion of promonocytic U-937 cells. Rapid inhibition of TNF-stimulated U-937 cell adhesion by AICAR was NO-dependent, associated with unaltered cell surface adhesion molecule expression, and reduced MCP-1 secretion by HAECs. In contrast, inhibition of TNF-stimulated U-937 cell adhesion by prolonged AMPK activation was NO-independent and associated with reduced cell surface adhesion molecule expression.

Conclusions— AMPK activation in HAECs inhibits TNF-stimulated leukocyte adhesion by a rapid NO-dependent mechanism associated with reduced MCP-1 secretion and a late NO-independent mechanism whereby adhesion molecule expression, in particular E-selectin, is suppressed.

We investigated the functional effects of AMPK activation in cultured human endothelial cells. Stimulation of AMPK inhibited TNF-stimulated monocyte adhesion by two distinct mechanisms: a rapid NO-dependent mechanism associated with a reduction in chemokine release and a late NO-independent mechanism whereby adhesion molecule expression is suppressed.

Key Words: AMP-activated protein kinase • endothelium • nitric oxide • adhesion