title: TLR4 regulates pulmonary vascular homeostasis and remodeling via redox signaling.
abstract: Pulmonary arterial hypertension (PAH) contributes to morbidity and mortality of patients with lung and heart diseases. We demonstrated that hypoxia induced PAH and increased pulmonary arterial wall thickness in wild-type mice. Mice deficient in toll-like receptor 4 (TLR4-/-) spontaneously developed PAH, which was not further enhanced by hypoxia. Echocardiography determined right ventricular hypertrophy and decreased pulmonary arterial acceleration time were associated with the development of PAH in TLR4(-/-) mice. In pulmonary arterial smooth muscle cells (PASMC), hypoxia decreased TLR4 expression and induced reactive oxygen species (ROS) and Nox1/Nox4. Inhibition of NADPH oxidase decreased hypoxia-induced proliferation of wild-type PASMC. PASMC derived from TLR4(-/-) mice exhibited increased ROS and Nox4/Nox1 expression. Our studies demonstrate an important role of TLR4 in maintaining normal pulmonary vasculature and in hypoxia-induced PAH. Inhibition of TLR4, by genetic ablation or hypoxia, increases the expression of Nox1/Nox4 and induces PASMC proliferation and vascular remodeling. These results support a novel function of TLR4 in regulating the development of PAH and reveal a new regulatory axis contributing to TLR4 deficiency-induced vascular hypertrophy and remodeling.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham AL 35294, *current address: Sun Yat-Sen Memorial Hospital ,Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham AL 35294.
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham AL 35294.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham AL 35294.
authors.forename: Yong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham AL 35294.
authors.forename: Nirag
authors.initials: N
authors.lastname: Jhala
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham AL 35294.
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Bradley
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham AL 35294; VA Medical Center, Birmingham AL 35294.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham AL 35294.
authors.forename: Sue
authors.initials: S
authors.lastname: Michalek
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham AL 35294; Department of Pediatric Dentistry, University of Alabama at Birmingham, Birmingham AL 35294.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham AL 35294.
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham AL 35294.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Benza
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294; VA Medical Center, Birmingham AL 35294, ybchen@uab.edu.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D001158:Arteries / Q000502:physiology*; D006439:Hemodynamics; D006706:Homeostasis / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000235:genetics; D008168:Lung / Q000098:blood supply*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D009249:NADP / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009249:NADP