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PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation.

Atherosclerosis is readily observed in regions of blood vessels where disturbed blood flow (d-flow) is known to occur. A positive correlation between protein kinase C ζ (PKCζ) activation and d-flow has been reported, but the exact role of d-flow-mediated PKCζ activation in atherosclerosis remains unclear. We tested the hypothesis that PKCζ activation by d-flow induces endothelial cell (EC) apoptosis by regulating p53. We found that d-flow-mediated peroxynitrite (ONOO(-)) increased PKCζ activation, which subsequently induced p53 SUMOylation, p53-Bcl-2 binding, and EC apoptosis. Both d-flow and ONOO(-) increased the association of PKCζ with protein inhibitor of activated STATy (PIASy) via the Siz/PIAS-RING domain (amino acids 301-410) of PIASy, and overexpression of this domain of PIASy disrupted the PKCζ-PIASy interaction and PKCζ-mediated p53 SUMOylation. En face confocal microscopy revealed increases in nonnuclear p53 expression, nitrotyrosine staining, and apoptosis in aortic EC located in d-flow areas in wild-type mice, but these effects were significantly decreased in p53(-/-) mice. We propose a novel mechanism for p53 SUMOylation mediated by the PKCζ-PIASy interaction during d-flow-mediated EC apoptosis, which has potential relevance to early events of atherosclerosis.

Pubmed ID: 21624955

Authors

  • Heo KS
  • Lee H
  • Nigro P
  • Thomas T
  • Le NT
  • Chang E
  • McClain C
  • Reinhart-King CA
  • King MR
  • Berk BC
  • Fujiwara K
  • Woo CH
  • Abe J

Journal

The Journal of cell biology

Publication Data

May 30, 2011

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL-064839
  • Agency: NHLBI NIH HHS, Id: HL-077789
  • Agency: NHLBI NIH HHS, Id: HL-102746
  • Agency: NIAAA NIH HHS, Id: R01 AA018016
  • Agency: NIAAA NIH HHS, Id: R01 AA018869

Mesh Terms

  • Animals
  • Apoptosis
  • Cells, Cultured
  • Endothelial Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Kinase C
  • Regional Blood Flow
  • SUMO-1 Protein
  • Sumoylation
  • Tumor Suppressor Protein p53