Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY 14642, USA.
J Cell Biol. 2011 May 30;193(5):867-84. doi: 10.1083/jcb.201010051.
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.
动脉粥样硬化在血管中血流紊乱（d-flow）的区域很容易观察到。已经报道了蛋白激酶 C ζ（PKCζ）的激活与 d-flow 之间存在正相关，但 d-flow 介导的 PKCζ 激活在动脉粥样硬化中的确切作用仍不清楚。我们检验了这样一个假设，即 d-flow 通过调节 p53 诱导内皮细胞（EC）凋亡。我们发现 d-flow 介导的过氧亚硝酸盐（ONOO(-)）增加了 PKCζ 的激活，随后诱导了 p53 的 SUMO 化、p53-Bcl-2 结合和 EC 凋亡。d-flow 和 ONOO(-) 都通过 PIASy 的 Siz/PIAS-RING 结构域（氨基酸 301-410）增加了 PKCζ 与蛋白抑制剂激活的 STATy（PIASy）的结合，而 PIASy 的这个结构域的过表达破坏了 PKCζ-PIASy 相互作用和 PKCζ 介导的 p53 SUMO 化。共聚焦显微镜检测到在野生型小鼠中，位于 d-flow 区域的主动脉 EC 中 p53 的非核表达、硝基酪氨酸染色和凋亡增加，但在 p53(-/-) 小鼠中这些效应明显减少。我们提出了一种新的机制，即 p53 SUMO 化是由 d-flow 介导的 EC 凋亡过程中 PKCζ-PIASy 相互作用介导的，这与动脉粥样硬化的早期事件有关。
