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Biochem Biophys Res Commun. 2008 May 23;370(1):159-63. doi: 10.1016/j.bbrc.2008.03.051. Epub 2008 Mar 19.

Fluid shear stress inhibits TNF-mediated JNK activation via MEK5-BMK1 in endothelial cells.

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1
Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Box 706, 601 Elmwood Avenue, Rochester, NY 14642, USA.

Abstract

Steady laminar blood flow protects vessels from atherosclerosis. We showed that flow decreased tumor necrosis factor-alpha (TNF)-mediated VCAM1 expression in endothelial cells (EC) by inhibiting JNK. Here, we determined the relative roles of MEK1, MEK5 and their downstream kinases ERK1/2 and BMK1 (ERK5) in flow-mediated inhibition of JNK activation. Steady laminar flow (shear stress=12dyn/cm(2)) increased BMK1 and ERK1/2 activity in EC. Pre-exposing EC for 10min to flow inhibited TNF activation of JNK by 58%. A key role for BMK1, but not ERK1/2 was shown. (1) Incubation of EC with PD184352, at concentrations that blocked ERK1/2, but not BMK1, had no effect on flow inhibition of TNF-mediated JNK activation. (2) BIX02188, a MEK5-selective inhibitor, completely reversed the inhibitory effects of flow. These findings indicate that flow inhibits TNF-mediated signaling events in EC by a mechanism dependent on activation of MEK5-BMK1, but not MEK1-ERK1/2. These results support a key role for the MEK5-BMK1 signaling pathway in the atheroprotective effects of blood flow.

PMID:
18358237
PMCID:
PMC2435412
DOI:
10.1016/j.bbrc.2008.03.051
[Indexed for MEDLINE]
Free PMC Article
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