Akira Yamauchi    Department   Kawasaki Medical School  Kawasaki Medical School, Department of Biochemistry,    Position   Professor
Article types	原著
Language	English
Peer review	Peer reviewed
Title	The downregulation of NADPH oxidase Nox4 during hypoxia in hemangioendothelioma cells: a possible role of p22phox on Nox4 protein stability.
Journal	Formal name：Free Radical Research Abbreviation：Free Radic Res ISSN code：10715762/10292470
Domestic / Foregin	Foregin
Volume, Issue, Page	55(9-10),pp.996-1004
Total page number	9
Author and coauthor	Miyano K, Okamoto S, Yamauchi A, Kawai C, Kajikawa M, Kiyohara T, Itsumi M, Taura M, Kuribayashi F.
Publication date	2022/01/11
Summary	NADPH oxidase (Nox) 4 produces H2O2 by forming a heterodimer with p22phox and is involved in hemangioendothelioma development through monocyte chemoattractant protein-1 (MCP-1) upregulation. Here, we show that Nox4 protein levels were maintained by p22phox in hemangioendothelioma cells and Nox4 protein stability was dependent on p22phox coexpression. Conversely, the degradation of Nox4 monomer was enhanced by p22phox knockdown. Under hypoxic conditions in hemangioendothelioma cells, p22phox was downregulated at the mRNA and protein levels. Downregulation of p22phox protein resulted in the enhanced degradation of Nox4 protein in hypoxia-treated hemangioendothelioma cells. In contrast, Nox2, a Nox isoform, was not altered at the protein level under hypoxic conditions. Nox2 exhibited a higher affinity for p22phox compared with Nox4, suggesting that when coexpressed with Nox4 in the same cells, Nox2 acts as a competitor. Nox2 knockdown restored Nox4 protein levels partially reduced by hypoxic treatment. Thus, Nox4 protein levels were attenuated in hypoxia-treated cells resulting from p22phox depletion. MCP-1 secretion was decreased concurrently with hypoxia-induced Nox4 downregulation compared with that under normoxia.