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Nox2 in regulatory T cells promotes angiotensin II–induced cardiovascular remodeling
Amber Emmerson, … , Giovanna Lombardi, Ajay M. Shah
Amber Emmerson, … , Giovanna Lombardi, Ajay M. Shah
Published April 24, 2018
Citation Information: J Clin Invest. 2018;128(7):3088-3101. https://doi.org/10.1172/JCI97490.
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Research Article Cardiology Immunology

Nox2 in regulatory T cells promotes angiotensin II–induced cardiovascular remodeling

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Abstract

The superoxide-generating enzyme Nox2 contributes to hypertension and cardiovascular remodeling triggered by activation of the renin-angiotensin system. Multiple Nox2-expressing cells are implicated in angiotensin II–induced (Ang II–induced) pathophysiology, but the importance of Nox2 in leukocyte subsets is poorly understood. Here, we investigated the role of Nox2 in T cells, particularly Tregs. Mice globally deficient in Nox2 displayed increased numbers of Tregs in the heart at baseline, whereas Ang II–induced effector T cell (Teff) infiltration was inhibited. To investigate the role of Treg Nox2, we generated a mouse line with CD4-targeted Nox2 deficiency (Nox2fl/flCD4Cre+). These animals showed inhibition of Ang II–induced hypertension and cardiac remodeling related to increased tissue-resident Tregs and reduction in infiltrating Teffs, including Th17 cells. The protection in Nox2fl/flCD4Cre+ mice was reversed by anti-CD25 antibody depletion of Tregs. Mechanistically, Nox2–/y Tregs showed higher in vitro suppression of Teff proliferation than WT Tregs, increased nuclear levels of FoxP3 and NF-κB, and enhanced transcription of CD25, CD39, and CD73. Adoptive transfer of Tregs confirmed that Nox2-deficient cells had greater inhibitory effects on Ang II–induced heart remodeling than WT cells. These results identify a previously unrecognized role of Nox2 in modulating suppression of Tregs, which acts to enhance hypertension and cardiac remodeling.

Authors

Amber Emmerson, Silvia Cellone Trevelin, Heloise Mongue-Din, Pablo D. Becker, Carla Ortiz, Lesley A. Smyth, Qi Peng, Raul Elgueta, Greta Sawyer, Aleksandar Ivetic, Robert I. Lechler, Giovanna Lombardi, Ajay M. Shah

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Figure 8

Effect of adoptive transfer of Nox2-deficient or WT Tregs on the response to Ang II infusion.

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Effect of adoptive transfer of Nox2-deficient or WT Tregs on the respons...
WT mice were treated with Ang II infusion (1.1 mg/kg/d, 14 days) by osmotic minipump. Immediately before minipump implantation, mice received 1 × 106 WT or Nox2–/y Tregs or saline control by i.v. injection. (A–C) Absolute numbers of CD45+TCR+CD4+ and CD45+TCR+CD8+ T cells and relative numbers of Tregs (CD25+FoxP3+) in the heart after 14 days of Ang II infusion. (D) Effect of adoptive transfer of Tregs on systolic BP. (E) Interstitial cardiac fibrosis in myocardial sections. Representative photomicrographs are shown to the right (scale bars: 50 μm) and mean data to the left. (F) Echocardiographic interventricular septal thickness (IVS) as a marker of left ventricular hypertrophy. (G) Cardiomyocyte cross-sectional area (CSA) in myocardial sections. *P < 0.05 for highlighted comparisons by 1-way ANOVA followed by Tukey’s post-test (A–C and E–G) or 2-way ANOVA (D); n = 5–8 per group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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