Role of Nox2 oxidase during the cardiac infiltration of T-cells in a model of hypertension

Abstract

Chronic hypertension related to increased activation of the renin-angiotensin system causes cardiac remodelling, which can progress to heart failure. Previous studies indicate that NADPH oxidase-2 (Nox2) activation is involved in angiotensin II (AngII)-induced hypertension and cardiovascular remodelling in mice. Nox2 is expressed in multiple cell types including cardiac myocytes, endothelial cells and inflammatory cells. The aim of this work was to investigate the role of T-cell Nox2 in the pathophysiology of AngII-induced cardiovascular remodelling.
Studies were undertaken in mice subjected to chronic AngII infusion with analysis of cardiac function, blood pressure, histology, and myocardial inflammatory cell infiltration (flow cytometry of single cell suspensions). In wild-type (WT) mice, AngII-induced increase in blood pressure was associated with a time dependant infiltration of T-cells into the myocardium. There was an increase in infiltration of anti-inflammatory regulatory T-cells (Tregs) into the myocardium and an increase in mRNA expression of the Treg transcription factor, FoxP3, as well as Treg cytokines and functional surface makers. In global Nox2 knockout (KO) animals, there was a reduction in immune cell infiltration into the myocardium associated with a blunting of AngII-induced hypertension. A novel CD4-targeted Nox2KO model was generated, in which AngII-induced hypertension was also blunted. These mice exhibited an increase in Tregs in the myocardium at baseline as compared to WT littermates, and showed no AngII-induced increase in Tregs. An adoptive transfer study was performed, in which Tregs from WT or global Nox2KO mice were injected via the tail vein into WT mice subsequently treated with AngII. AngII-induced hypertension was significantly blunted in WT-Treg treated mice and an even greater effect was observed in KO-Treg treated mice. Cardiomyocyte hypertrophy was also blunted in these animals. Flow cytometry revealed lower cardiovascular inflammation in both Treg treated groups, especially in the Nox2KO-Treg treated group. Furthermore, in vitro Treg suppression assays revealed that Nox2KO-Tregs were significantly more suppressive than WT-Tregs.
These data reveal that myocardial T-cell, specifically CD4+ T-cell, infiltration is a feature of AngII-induced hypertension and is regulated by Nox2. Moreover, Nox2 modulates Treg suppressive function, with significant impact on the development of hypertension and cardiac remodelling. Taken together, these studies identify an important role for T-cell Nox2 in the pathophysiology of AngII-induced hypertension and cardiovascular remodelling.

Date of Award	2016
Original language	English
Awarding Institution	King's College London
Supervisor	Giovanna Lombardi (Supervisor) & Ajay Shah (Supervisor)