Differential roles of PKCα and PKC in controlling the gene expression of Nox4 in human endothelial cells

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• 作者：Hui Xu ; Claudia Goettsch ; Ning Xia ; Sven Horke ; Henning Morawietz ; Ulrich Fö ; rstermann ; Huige Li
• 关键词：Endothelium ; Gene expression ; Reactive oxygen species ; NADPH oxidase ; Protein kinase C ; Free radicals
• 刊名：Free Radical Biology and Medicine
• 出版年：2008
• 出版时间：15 April 2008
• 年：2008
• 卷：44
• 期：8
• 页码：1656-1667
• 全文大小：1220 K

文摘

NADPH oxidases are major sources of superoxide in the vascular wall. This study investigates the role of protein kinase C (PKC) in regulating gene expression of NADPH oxidases. Treatment of human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 endothelial cells with phorbol 12-myristate 13-acetate (PMA) or phorbol 12,13-dibutyrate led to a PKC-dependent biphasic expression of the gp91phox homolog Nox4. A downregulation of Nox4 was observed at 6 h and an upregulation at 48 h after phorbol ester treatment. The early Nox4 downregulation was associated with a reduced superoxide production, whereas the late Nox4 upregulation was accompanied by a clear enhancement of superoxide. PMA activated the PKC isoforms and in HUVEC and EA.hy 926 cells. Knockdown of PKC by siRNA prevented the early downregulation of Nox4, whereas knockdown of PKC selectively abolished the late Nox4 upregulation. Vascular endothelial growth factor (VEGF), which activates PKC but not PKC in HUVEC, increased Nox4 expression without the initial downregulation. VEGF-induced Nox4 upregulation was associated with an enhanced proliferation and angiogenesis of HUVEC. Both effects could be reduced by inhibition of NADPH oxidase. Thus, a selective inhibition/knockdown of PKC may represent a novel therapeutic strategy for vascular disease.