title: Eotaxin-2 increased toll-like receptor 4 expression in endothelial cellsin vitroand exacerbates high-cholesterol diet-induced atherogenesisin vivo.
abstract: Eotaxin-2 is a potent chemoattractant. High concentration of eotaxin-2 triggers the inflammation and tumor metastasis. Inhibition of eotaxin-2 may protect experimental atherogenesis although the mechanism is still unclear. Toll-like receptor 4 (TLR4) plays a major role mediating vascular inflammation, which is related to atherogenesis. In the results, we demonstrated that eotaxin-2 potentially impairs the tube formation capacity of human coronary artery endothelial cells (HCAECs). Eotaxin-2 augments the monocytic adhesion in lipopolysaccharides (LPS)-induced HCAECs, and which were reversed by TLR4 siRNA. Thus this study was conducted to investigate whether eotaxin-2 increases TLR4 expression, and then enhances the sensitivity of cells to antigen stimulation in HCAECs, which mediates the increasing of the development of serious atherosclerosis. In fact, we showed that JNK/SAPK, p38 MAPK, and ERK1/2 activation contribute to the transcriptional signaling pathway, JNK/SAPK and p38 MAPK regulate post-transcriptional modification, as well as protein-trafficking pathway in eotaxin-2-treated HCAECs TLR4 expression. RNA binding proteins, such as human antigen R (HuR) and tristetraprolin (TTP) mediate stability of TLR4 mRNA and chaperone, such as PRAT4A (a protein associated with TLR4) regulate trafficking of TLR4 protein might confer eotaxin-2 responsiveness. Eotaxin-2 administration led to a significant elevation of high cholesterol diet-induced atherosclerosis, and of TLR4 expression in B6.129S7-Ldlrtm1Her/J but notLdlr-/--/-/Tlr4-/-mice. Our results revealed that eotaxin-2 induced overexpression TLR4 via mitogen-activated protein kinases (MAPK) signaling pathways, RNA binding proteins-mediated mRNA stabilization, and PRAT4A-regulated trafficking in HCAECs. These effects may lead to amplification of inflammatory responses contribute to the pathogenesis of cardiovascular disorders.
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Taoyuan Armed Forces General HospitalTaoyuan, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General HospitalTaipei, Taiwan; Department and Graduate Institute of Pharmacology, National Defense Medical CenterTaipei, Taiwan.
authors.forename: Chien-Sung
authors.initials: CS
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University HospitalTaipei, Taiwan.
authors.forename: Chun-Yao
authors.initials: CY
authors.lastname: Huang
authors.affiliation: School of Medical Laboratory Science and Biotechnology Taipei Medical University Taipei, Taiwan.
authors.forename: Chien-Ho
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General HospitalTaipei, Taiwan; Institute of Oral Biology, National Yang-Ming UniversityTaipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University HospitalTaipei, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Shih
authors.affiliation: Division of Cardiovascular Surgery, Taipei Medical University Hospital Taipei, Taiwan.
authors.forename: Nai-Wen
authors.initials: NW
authors.lastname: Tsao
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University HospitalTaipei, Taiwan.
authors.forename: Kuang-Hsing
authors.initials: KH
authors.lastname: Chiang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, China Medical University Taichung, Taiwan.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Division of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University Taipei, Taiwan.
authors.forename: Hellen
authors.initials: H
authors.lastname: Jeng
authors.affiliation: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical UniversityTaipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University HospitalTaipei, Taiwan.
authors.forename: Feng-Yen
authors.initials: FY
authors.lastname: Lin
keywords: Eotaxin-2; atherosclerosis; endothelial cells; toll-like receptor 4