Background; C-reactive protein (CRP) triggers inflammatory responses and apoptotic changes of vascular smooth muscle cells (VSMCs), however, the involved mechanism is not clear. Results; 1. RT-PCR, flow cytometry, and immunoblotting assay showed that cultured VSMCs isolated from human coronary artery express FcgammaRIIa, a main isoform of CD32. FcgammaRIIa expressed in VSMCs was upregulated by CRP. Immunohistochemistry and immunofluorescence staining of human coronary artery plaque showed the co-localization of FcgammaRIIa with 慣 actin (+) VSMCs in neointimal region. 2. Confocal microscopic image analysis of H2DCFDA-labeled cells showed that CRP dose-dependently induced generation of intracellular reactive oxygen species (ROS) by human VSMCs and FcgammaRIIa-transfected 293FT cells. The CRP-induced ROS generation by VSMCs was completely inhibited by a specific antibody against FcRIIa. 3. Real-time PCR showed that human VSMCs mainly express NADPH oxidase (Nox) isoform 4. Pull down assay showed that CRP immediately generated GTP-Rac, an essential component of active NADPH oxidase complex. The functional inhibition of NADPH oxidase through transfecting Nox4-specific siRNA or p22phox-specific decoy oligomers abolished CRP-induced ROS generation. 4. The suppression of NADPH oxidase activities significantly reduced the degree of AP-1 and NF-觀B activation, mRNA expression levels of MCP-1, IL-6, and ET-1, as determined by real-time PCR. TUNEL assay showed that the suppression of NADPH oxidase activities profoundly reduced the number of VSMCs undergoing apoptotic changes in response to CRP. Conclusions; CRP-induced ROS generation by VSMCs, which requires functional activation of FcgammaRIIa and subsequent NADPH oxidase activation, orchestrates pro-inflammatory activities and apoptotic changes of VSMCs and may eventually promote atherogenesis and plaque rupture.