The role of Nox2 containing NADPH oxidase in hypertensive heart disease

NADPH oxidases are a family of reactive oxygen species generating enzymes which are implicated in cardiovascular pathophysiology. The Nox2-based NADPH oxidase has been reported to be involved in the development of cardiac hypertrophy and fibrosis. However the relevant cellular source(s) involved in the above effects remains unclear. The aim of this thesis was to investigate the critical cell source of the Nox2 in a model of angiotensin II (AngII) induced left ventricular hypertrophy (LVH) and fibrosis.<br/>ROS production in resident cardiac fibroblasts was stimulated by AngII, aldosterone and TGFβ to investigate cardiac fibroblasts as a crucial cell source for Nox2. Only TGFβ elicited a Nox2 dependent ROS response thus placing Nox2 downstream of TGFβ. As AngII stimulates cardiac fibrosis and hypertrophy via downstream TGFβ, resident cardiac fibroblasts could be another critical cell source for Nox2 in the development of cardiac fibrosis and hypertrophy.<br/>The importance of Nox2 in macrophages/monocytes (peripheral circulating cell) migration was investigated by way of Dunn Chambers. Nox2 was shown to be crucial in the chemotaxis of these cells towards CSF-1 stimulation. Also the speed and persistence of their migration was significantly reduced following the loss of Nox2.<br/>Chimeric mice (WT mice with Nox2-/- marrow and Nox2-/- mice with WT marrow) were generated in-house by lethal radiation and marrow rescue with cells from mice of different genotype. Following AngII stimulation the chimeric mice demonstrated a hypertensive response. The loss of Nox2 in the circulating cells prevented the development of left ventricular hypertrophy suggesting that the peripheral circulating cells were a critical cell source for Nox2 in the development of cardiac hypertrophy. The loss of Nox2 in the resident cardiac cells prevented the development of cardiac fibrosis thus suggesting that the resident cardiac cells were the critical cell source for Nox2 in the development of cardiac fibrosis.<br/>These results indicate that Nox2 has a cell specific role in the development of cardiac fibrosis and hypertrophy following AngII stimulation.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Chaubey, Sanjay

Advisors dc:contributor.advisor

• Shah, Ajay Manmohan
• Cave, Alison Christine

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/691db05e-7405-46da-810f-e8a9485c77c2

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/691db05e-7405-46da-810f-e8a9485c77c2