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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Circulation*
  • Cattle
  • Cells, Cultured
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / enzymology*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase 5 / antagonists & inhibitors
  • MAP Kinase Kinase 5 / metabolism*
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase 7 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Shear Strength
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 7
  • MAP Kinase Kinase 5