title: Toll-Like Receptor 4 Is Essential in the Development of Abdominal Aortic Aneurysm.
abstract: Toll-like receptor (TLR) family plays a key role in innate immunity and various inflammatory responses. TLR4, one of the well-characterized pattern-recognition receptors, can be activated by endogenous damage-associated molecular pattern molecules such as high mobility group box 1 (HMGB1) to sustain sterile inflammation. Evidence suggested that blockade of TLR4 signaling may confer protection against abdominal aortic aneurysm (AAA). Herein we aimed to obtain further insight into the mechanism by which TLR4 might promote aneurysm formation. Characterization of the CaCl2-induced AAA model in mice revealed that upregulation of TLR4 expression, localized predominantly to vascular smooth muscle cells (VSMCs), was followed by a late decline during a 28-day period of AAA development. In vitro, TLR4 expression was increased in VSMCs treated with HMGB1. Knockdown of TLR4 by siRNA attenuated HMGB1-enhanced production of proinflammatory cytokines, specifically interleukin-6 and monocyte chemoattractant protein-1 (MCP-1), and matrix-degrading matrix metalloproteinase (MMP)-2 from VSMCs. In vivo, two different strains of TLR4-deficient (C57BL/10ScNJ and C3H/HeJ) mice were resistant to CaCl2-induced AAA formation compared to their respective controls (C57BL/10ScSnJ and C3H/HeN). Knockout of TLR4 reduced interleukin-6 and MCP-1 levels and HMGB1 expression, attenuated macrophage accumulation, and eventually suppressed MMP production, elastin destruction and VSMC loss. Finally, human AAA exhibited higher TLR4 expression that was localized to VSMCs. These data suggest that TLR4 signaling contributes to AAA formation by promoting a proinflammatory status of VSMCs and by inducing proteinase release from VSMCs during aneurysm initiation and development.
authors.affiliation: Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chao-Han
authors.initials: CH
authors.lastname: Lai
authors.affiliation: Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Kuan-Chieh
authors.initials: KC
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Fang-Tzu
authors.initials: FT
authors.lastname: Lee
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hung-Wen
authors.initials: HW
authors.lastname: Tsai
authors.affiliation: Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Ma
authors.affiliation: Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Tsung-Lin
authors.initials: TL
authors.lastname: Cheng
authors.affiliation: Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Bi-Ing
authors.initials: BI
authors.lastname: Chang
authors.affiliation: Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Guey-Yueh
authors.initials: GY
authors.lastname: Shi
authors.affiliation: Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Wu
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000378:metabolism*; D002122:Calcium Chloride; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C000593873:Ager protein, mouse; D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020782:Matrix Metalloproteinases; D002122:Calcium Chloride