Copyright © 2007, European Society of Cardiology
Fc
RIIa mediates C-reactive protein-induced inflammatory responses of human vascular smooth muscle cells by activating NADPH oxidase 4
Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
* Corresponding author. Asan Medical Center, 388-1 Pungnap-2 dong Songpa-gu 138-736, Seoul, South Korea. Tel.: +82 2 3010 3150; fax: +82 2 486 5918. steadyhan{at}amc.seoul.kr
Objectives We investigated the mechanism by which C-reactive protein (CRP) affects pro-inflammatory activities of vascular smooth muscle cells (VSMCs).
Methods and results RT-PCR, flow cytometry, and immunoblotting assays consistently showed the expression of Fc
RIIa by cultured VSMCs isolated from human coronary arteries. Immunofluorescence staining of human coronary artery plaque showed the co-localization of FcRIIa with 
-actin(+) VSMCs in atheromatous regions. Confocal microscopic image analysis of H2DCFDA-labeled cells showed that CRP induced intracellular reactive oxygen species (ROS) generation by FcRIIa(+) HEK293T cells. Moreover, CRP time- and dose-dependently generated ROS in VSMCs through FcRIIa activation. VSMCs mainly express NADPH oxidase 4 isoform (Nox4), the suppression of which using a specific siRNA completely abolished CRP-induced ROS generation by VSMCs. The downregulation of p22phox, a component of the active Nox4 complex, by transfecting with specific decoy oligomers and functional blocking of FcRIIa not only inhibited the CRP-induced ROS generation but also reduced the degree of AP-1 and NF-
B activation, the production of MCP-1, IL-6, and ET-1, and the apoptotic changes of VSMCs in response to CRP.
Conclusions CRP-induced ROS generation by VSMCs, which requires functional activation of FcRIIa and NADPH oxidase 4, orchestrates pro-inflammatory activities of VSMCs and may eventually promote atherogenesis and plaque rupture.
KEYWORDS C-reactive protein; Atherosclerosis; Vascular smooth muscle cells; Receptors (FcRIIa); Cytokines; Apoptosis
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