PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation

Kyung-Sun Heo, Hakjoo Lee, Patrizia Nigro, Tamlyn Thomas, Nhat-Tu Le, Eugene Chang, Carolyn McClain, Cynthia A Reinhart-King, Michael R King, Bradford C Berk, Keigi Fujiwara, Chang-Hoon Woo, Jun-ichi Abe

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)867-84
Number of pages18
JournalJournal of Cell Biology
Volume193
Issue number5
DOIs
StatePublished - May 30 2011

Keywords

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

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