Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction

Circ J. 2011;75(12):2722-30. doi: 10.1253/circj.cj-11-1124. Epub 2011 Nov 10.

Abstract

Emerging evidence is revealing the different roles of steady laminar flow (s-flow) and disturbed flow (d-flow) in the regulation of the vascular endothelium. s-flow is atheroprotective while d-flow creates an atheroprone environment. Most recently, we found unique atheroprone signals, which involve protein kinase C (PKC)ζ activation, elicited by d-flow. We and others have defined a novel role for PKCζ as a shared mediator for tumor necrosis factor alpha (TNF alpha) and d-flow, which cause pro-inflammatory and pro-apoptotic events in endothelial cells (ECs) in the atheroprone environment. Under such conditions, ONOO(-) formation is increased in a d-flow-mediated PKCζ-dependent manner. Here, we propose a new signaling pathway involving d-flow-induced EC inflammation via PKCζ-ERK5 interaction-mediated downregulation of KLF2/eNOS stability, which leads to PKCζ-mediated p53-SUMOylation and EC apoptosis. In addition, we highlight several mechanisms contributing to endothelial dysfunction, focusing on the relations between flow patterns and activation of reactive oxygen species generating enzymes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis*
  • Atherosclerosis / blood*
  • Atherosclerosis / pathology
  • Atherosclerosis / physiopathology
  • Blood Flow Velocity
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Enzyme Activation
  • Enzyme Stability
  • Humans
  • Inflammation / blood
  • Inflammation / pathology
  • Inflammation / physiopathology
  • Isoenzymes / metabolism
  • Kruppel-Like Transcription Factors / metabolism
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Protein Kinase C / metabolism
  • Protein Kinase C-theta
  • Reactive Oxygen Species / blood*
  • Signal Transduction*
  • Sumoylation
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Isoenzymes
  • KLF2 protein, human
  • Kruppel-Like Transcription Factors
  • Reactive Oxygen Species
  • TP53 protein, human
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • PRKCQ protein, human
  • Protein Kinase C
  • Protein Kinase C-theta
  • Mitogen-Activated Protein Kinase 7