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 9

Scavenging superoxide or isoketals prevents aortic collagen deposition, aortic stiffening and hypertension in tgsm/p22phox mice.

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Scavenging superoxide or isoketals prevents aortic collagen deposition, ...
Tgsm/p22phox mice received either no treatment, tempol, or 2-HOBA in the drinking water from 3–9 months of age. (A) Masson’s trichrome staining at ×20 magnification. Scale bars: 100 μm. (B and C) Mean data for quantification of collagen staining (B) and hydroxyproline content (C). *P < 0.05; **P < 0.01. (D and E) Pressure diameter and stress strain relationships for isolated aortic segments studied as in Figure 1. ##P < 0.01 vs. WT; **P < 0.01 vs. 2-HOBA. (F and G) Effect of antioxidant treatment on blood pressure in aged tgsm/p22phox mice. Collagen deposition was quantified using 1-way ANOVA. Aortic stiffness and blood pressure were analyzed with 1-way ANOVA with repeated measurements (n = 6–8).