Immune activation caused by vascular oxidation promotes fibrosis and hypertension
Jing Wu, … , Meena S. Madhur, David G. Harrison
Jing Wu, … , Meena S. Madhur, David G. Harrison
Published November 23, 2015
Citation Information: J Clin Invest. 2016;126(1):50-67. https://doi.org/10.1172/JCI80761.
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Research Article Aging Cardiology Immunology Inflammation Nephrology Vascular biology

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 (tgsm/p22phox mice, which overexpress the NADPH oxidase subunit p22phox 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 tgsm/p22phox mice produced high levels of IL-17A and IFN-γ. Crossing tgsm/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 tgsm/p22phox mice. Autologous pulsing with tgsm/p22phox aortic homogenates promoted DCs of tgsm/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

Jing Wu, Mohamed A. Saleh, Annet Kirabo, Hana A. Itani, Kim Ramil C. Montaniel, Liang Xiao, Wei Chen, Raymond L. Mernaugh, Hua Cai, Kenneth E. Bernstein, Jörg J. Goronzy, Cornelia M. Weyand, John A. Curci, Natalia R. Barbaro, Heitor Moreno, Sean S. Davies, L. Jackson Roberts II, Meena S. Madhur, David G. Harrison

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Figure 11

Cytokine production of T cells in the spleen of mice with chronic vascular oxidative stress.

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Cytokine production of T cells in the spleen of mice with chronic vascul...
(A) Gating strategy for identifying T cell populations among total spleenocytes. Single cell suspensions were prepared from freshly isolated mouse spleens via enzymatic digestion and mechanical dissociation. (B–I) Intracellular staining indicating IL-17A (B, D–F) and IFN-γ (C, G–I) production in T cell subsets in WT and Tgsm/p22phox mice. Bar graphs were analyzed using 1-way ANOVA (n = 5–7). **P < 0.01.