title: Immune activation caused by vascular oxidation promotes fibrosis and hypertension.
abstract: Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tg(sm/p22phox) mice, which overexpress the NADPH oxidase subunit p22(phox) in smooth muscle, and mice with vascular-specific deletion of extracellular SOD) and have shown that these animals develop vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension with age. T cells from tg(sm/p22phox) mice produced high levels of IL-17A and IFN-γ. Crossing tg(sm/p22phox) mice with lymphocyte-deficient Rag1(-/-) mice eliminated vascular inflammation, aortic stiffening, renal dysfunction, and hypertension; however, adoptive transfer of T cells restored these processes. Isoketal-protein adducts, which are immunogenic, were increased in aortas, DCs, and macrophages of tg(sm/p22phox) mice. Autologous pulsing with tg(sm/p22phox) aortic homogenates promoted DCs of tg(sm/p22phox) mice to stimulate T cell proliferation and production of IFN-γ, IL-17A, and TNF-α. Treatment with the superoxide scavenger tempol or the isoketal scavenger 2-hydroxybenzylamine (2-HOBA) normalized blood pressure; prevented vascular inflammation, aortic stiffening, and hypertension; and prevented DC and T cell activation. Moreover, in human aortas, the aortic content of isoketal adducts correlated with fibrosis and inflammation severity. Together, these results define a pathway linking vascular oxidant stress to immune activation and aortic stiffening and provide insight into the systemic inflammation encountered in common vascular diseases.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.forename: Annet
authors.initials: A
authors.lastname: Kirabo
authors.forename: Hana A
authors.initials: HA
authors.lastname: Itani
authors.forename: Kim Ramil C
authors.initials: KR
authors.lastname: Montaniel
authors.forename: Liang
authors.initials: L
authors.lastname: Xiao
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Mernaugh
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Bernstein
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
authors.forename: John A
authors.initials: JA
authors.lastname: Curci
authors.forename: Natalia R
authors.initials: NR
authors.lastname: Barbaro
authors.forename: Heitor
authors.initials: H
authors.lastname: Moreno
authors.forename: Sean S
authors.initials: SS
authors.lastname: Davies
authors.forename: L Jackson
authors.initials: LJ
authors.lastname: Roberts
authors.forename: Meena S
authors.initials: MS
authors.lastname: Madhur
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
mesh_terms: D000367:Age Factors; D000818:Animals; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005355:Fibrosis; D006801:Humans; D006973:Hypertension / Q000209:etiology*; D007249:Inflammation / Q000150:complications*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D013601:T-Lymphocytes / Q000502:physiology; D059289:Vascular Stiffness; D014657:Vasculitis / Q000150:complications
chemical_list: D016207:Cytokines; D003094:Collagen