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 January 4, 2016; First 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 13

Role of isoketal and oxidation in aortic collagen deposition and stiffening in humans.

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Role of isoketal and oxidation in aortic collagen deposition and stiffen...
(A–D) Data from human aortas. (E) Comparison of PWV and isoprostane content in patients. Consecutive 6 μm sections were stained with anti-CD3, D-11 ScFv, and Masson’s trichrome blue (A). Images are ×20 magnification. Scale bars: 100 μm. Image J was used to quantify the area of D-11 staining for isoketal adducts and the area of blue in the Masson’s trichrome stains. Human T cells were quantified by counting positively stained cells per ×20 field (B and C). Spearman’s correlations comparing PWV and 8-isoprostanes in normotensive and treated hypertensive humans (E). M, media; A, adventitia.