title: TLR4 is a critical regulator of angiotensin II-induced vascular remodeling: the roles of extracellular SOD and NADPH oxidase.
abstract: Toll-like receptor 4 (TLR4) and angiotensin II (AngII) induce vascular remodeling through the production of reactive oxygen species (ROS). AngII has also been shown to increase antioxidant enzyme extracellular superoxide dismutase (ecSOD). However, the roles of TLR4 in Ang II-induced ROS production, vascular remodeling and hypertension remain unknown. Mice lacking TLR4 function showed significant inhibition of vascular remodeling in response to chronic AngII infusion, with no impact on blood pressure. The increases in ROS level and NADPH oxidase activity in response to AngII infusion were markedly blunted in TLR4-deficient mice. Similar effects were observed in wild-type (WT) mice treated with a sub-depressor dose of the AT1 receptor antagonist irbesartan, which had no effects on TLR4-deficient mice. Intriguingly, the AngII infusion-induced increases in ecSOD activity and expression were rather enhanced in TLR4-deficient mice compared with WT mice, whereas the expression of the proinflammatory chemokine MCP-1 was decreased. Importantly, AngII-induced vascular remodeling was positively correlated with NADPH oxidase activity, ROS levels and MCP-1 expression levels. Notably, chronic norepinephrine infusion, which elevates blood pressure without increasing ROS production, did not induce significant vascular remodeling in WT mice. Taken together, these findings suggest that ROS elevation is required for accelerating vascular remodeling but not for hypertensive effects in this model. We demonstrated that TLR4 plays a pivotal role in regulating AngII-induced vascular ROS levels by inhibiting the expression and activity of the antioxidant enzyme ecSOD, as well as by activating NADPH oxidase, which enhances inflammation to facilitate the progression of vascular remodeling.
authors: Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Tadaaki
authors: T
authors: Nakashima
authors: Center for Clinical Research, Yamaguchi University Hospital, Yamaguchi, Japan.
authors: Seiji
authors: S
authors: Umemoto
authors: Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Koichi
authors: K
authors: Yoshimura
authors: Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Susumu
authors: S
authors: Matsuda
authors: Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Shinichi
authors: S
authors: Itoh
authors: Institute of Experimental Animals, Science Research Center, Yamaguchi University, Yamaguchi, Japan.
authors: Tomoaki
authors: T
authors: Murata
authors: Department of Medicine and Pharmacology, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IL, USA.
authors: Tohru
authors: T
authors: Fukai
authors: Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Masunori
authors: M
authors: Matsuzaki
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000473:pathology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D000077405:Irbesartan; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017382:Reactive Oxygen Species; D013777:Tetrazoles; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D000077405:Irbesartan; D009638:Norepinephrine