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- Title
Immune activation caused by vascular oxidation promotes fibrosis and hypertension.
- Authors
Jing Wu; Saleh, Mohamed A.; Kirabo, Annet; Itani, Hana A.; Montaniel, Kim Ramil C.; Liang Xiao; Wei Chen; Mernaugh, Raymond L.; Hua Cai; Bernstein, Kenneth E.; Goronzy, Jörg J.; Weyand, Cornelia M.; Curci, John A.; Barbaro, Natalia R.; Moreno, Heitor; Davies, Sean S.; Roberts II, L. Jackson; Madhur, Meena S.; Harrison, David G.; Wu, Jing
- 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.
- Subjects
REACTIVE oxygen species; NADPH oxidase; SMOOTH muscle physiology; VASCULAR diseases; T cells; INTERFERON gamma; INTERLEUKIN-17; LABORATORY mice; AGE distribution; ANIMAL experimentation; CARDIOVASCULAR system physiology; COLLAGEN; CYTOKINES; HYPERTENSION; INFLAMMATION; MICE; RESEARCH funding; VASCULITIS; OXIDATIVE stress; FIBROSIS; DISEASE complications; METABOLISM; PHYSIOLOGY
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 1, p50
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI80761