Inhibition of reactive oxygen species generation attenuates TLR4-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells

• Published in: Laboratory investigation Vol. 93; no. 8; pp. 880 - 887
• Main Authors: Pi, Yan, Zhang, Li-li, Li, Bing-hu, Guo, Lu, Cao, Xiao-jie, Gao, Chang-yue, Li, Jing-cheng
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.08.2013; Nature Publishing Group US; Nature Publishing Group
• Subjects: 631/250/256; 631/250/262/2106/2108; 692/699/75/593; Acetophenones - pharmacology; Animals; Becaplermin; Carotid Artery Injuries - etiology; Carotid Artery Injuries - metabolism; Carotid Artery Injuries - pathology; Cell Proliferation - drug effects; Cells, Cultured; Hyperplasia - chemically induced; inflammation; intimal hyperplasia; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Neointima - metabolism; Oxidative Stress - drug effects; Pathology; Phenotype; Proto-Oncogene Proteins c-sis - pharmacology; reactive oxygen species; Reactive Oxygen Species - metabolism; research-article; Toll-like receptor 4; Toll-Like Receptor 4 - metabolism; vascular smooth muscle cell; intimal hyperplasia; vascular smooth muscle cell; inflammation; reactive oxygen species; Toll-like receptor 4
• DOI: 10.1038/labinvest.2013.79
• ISSN: 0023-6837; 1530-0307

Reactive oxygen species (ROS) are associated with inflammation and vasculature dysfunction. This study aimed to investigate the potential role of the ROS on vascular Toll-like receptor 4 (TLR4)-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells (VSMCs). A wire-induced carotid injury model was used in male TLR4-deficient (TLR4−/−) and wild-type C57BL/6J mice to induce neointima formation. In the presence or absence of the ROS scavenger apocynin for 14 days, increased TLR4 and proinflammatory cytokines were observed in wire injury-induced carotid neointima and in platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMCs. The TLR4−/− protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to PDGF-BB. Apocynin attenuated intimal hyperplasia. Pre-treatment with apocynin significantly inhibited intracellular ROS generation, accompanied by a significant suppression of TLR4 and proinflammatory cytokines expression, and VSMC proliferation and migration. However, the results were not obvious in TLR4−/− condition. These findings highlight the importance of ROS inhibition in TLR4-mediated proinflammatory and proliferative phenotype of VSMCs, and suggest ROS as an essential therapeutic target for TLR4-associated vascular inflammation and vascular diseases.