Role of NADPH oxidase 4 in lipopolysaccharide-induced proinflammatory responses by human aortic endothelial cells

doi:10.1016/j.cardiores.2006.09.012

Cardiovascular Research 2006 72(3):447-455; doi:10.1016/j.cardiores.2006.09.012

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Role of NADPH oxidase 4 in lipopolysaccharide-induced proinflammatory responses by human aortic endothelial cells

Hye Sun Park^a^,1, Jung Nyeo Chun^a^,1, Hye Young Jung^a, Chulhee Choi^b^,* and Yun Soo Bae^a^,*

^aDivision of Molecular Life Sciences, Center for Cell Signaling Research, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul 120-750, Republic of Korea
^bDepartment of Biosystems, Korea Advanced Institute of Science and Technology, 373-1 Guseong-Dong, Yuseong-Gu, Daejeon, Republic of Korea

^* Corresponding authors. Bae is to be contacted at Tel.: +82 2 3277 2729; fax: +82 2 3277 3760. Choi, Tel.: +82 42 869 4321; fax: +82 42 869 4310. Email address: cchoi{at}kaist.ac.kr baeys{at}ewha.ac.kr

Objective: We investigated the role of NADPH oxidase 4 (Nox4)on lipopolysaccharide (LPS)-induced proinflammatory responsesby human aortic endothelial cells (HAECs).

Methods and results: Yeast two-hybrid and glutathione-S-transferasepull-down assays indicated that the cytosolic Toll/IL-1R regionof Toll-like receptor 4 (TLR4) (amino acids 739–769) isthe responsible domain for interaction with the COOH terminalof Nox4 (amino acids 451–530). Consistently, overexpressionof the COOH-terminal region of Nox4 inhibited nuclear factor- ${kappa}$ Bactivation in response to LPS. Downregulation of Nox4 by transfectionof siRNA specific to Nox4 in HAECs resulted in a failure toinduce reactive oxygen species (ROS) generation and subsequentexpression of intercellular adhesion molecule-1 (ICAM-1) andchemokines such as IL-8 and monocyte chemoattractant protein-1(MCP-1) in response to LPS. Furthermore, transient transfectionof endothelial cells with Nox4 siRNA led to a decrease in migrationand adhesion of monocytes in response to LPS by 36% and 52%,respectively.

Conclusions: Nox4 plays a central role in LPS-induced proinflammatoryresponses by endothelial cells in an ROS-dependent manner.

KEYWORDS NADPH oxidase 4; Toll-like receptor 4; Lipopolysaccharide; Reactive oxygen species; Endothelial cells; Atherosclerosis

¹ Both authors contributed equally to this work.

Time for primary review 38 days

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