title: PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation.
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.
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Heo
authors.forename: Hakjoo
authors.initials: H
authors.lastname: Lee
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nigro
authors.forename: Tamlyn
authors.initials: T
authors.lastname: Thomas
authors.forename: Nhat-Tu
authors.initials: NT
authors.lastname: Le
authors.forename: Eugene
authors.initials: E
authors.lastname: Chang
authors.forename: Carolyn
authors.initials: C
authors.lastname: McClain
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Reinhart-King
authors.forename: Michael R
authors.initials: MR
authors.lastname: King
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
authors.forename: Keigi
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Abe
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000378:metabolism*; D012039:Regional Blood Flow; D025842:SUMO-1 Protein / Q000378:metabolism; D058207:Sumoylation; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D011493:Protein Kinase C; D025842:SUMO-1 Protein; D016159:Tumor Suppressor Protein p53; D000099221:Protein Kinase C zeta