Low shear stress preferentially enhances IKK activity through selective sources of ROS for persistent activation of NF-κB in endothelial cells

Sumathy Mohan, Koichi Koyoma, Amalraj Thangasamy, Hiroyasu Nakano, Randolph D. Glickman, Natarajan Mohan

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

NF-κB signaling pathway has been known to play a major role in the pathological process of atherogenesis. Unlike high shear stress, in which the NF-κB activity is transient, our earlier studies have demonstrated a persistent activation of NF-κB in response to low shear stress in human aortic endothelial cells. These findings partially explained why low shear regions that exist at bifurcations of arteries are prone to atherosclerosis, unlike the relatively atheroprotective high shear regions. In the present study, we further investigated 1) the role of NF-κB signaling kinases (IKKα and β) that may be responsible for the sustained activation of NF-κB in low shear stress and 2) the regulation of these kinases by reactive oxygen species (ROS). Our results demonstrate that not only is a significant proportion of low shear-induced-kinase activity is contributed by IKKβ, but it is also persistently induced for a prolonged time frame. The IKK activity (both α and β) is blocked by apocynin (400 μM), a specific NADPH oxidase inhibitor, and diphenyleneiodonium chloride (DPI; 10 μM), an inhibitor of flavin-containing oxidases like NADPH oxidases. Determination of ROS also demonstrated an increased generation in low shear stress that could be blocked by DPI. These results suggest that the source of ROS generation in endothelial cells in response to low shear stress is NADPH oxidase. The DPI-inhibitable component of ROS is the primary regulator of specific upstream kinases that determine the persistent NF-κB activation selectively in low shear-induced endothelial cells.

Original languageEnglish (US)
Pages (from-to)C362-C371
JournalAmerican Journal of Physiology - Cell Physiology
Volume292
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • Atherogenesis
  • Laminar shear stress
  • Oxidative stress
  • Reactive oxygen species
  • Upstream κB kinases

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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