Nox4 regulates Nrf2 and glutathione redox in cardiomyocytes in vivo

Abstract

NADPH oxidase-4 (Nox4) is an important modulator of redox signaling that is inducible at the level of transcriptional expression in multiple cell types. By contrast to other Nox enzymes, Nox4 is continuously active without requiring stimulation. We reported recently that expression of Nox4 is induced in the adult heart as an adaptive stress response to pathophysiological insult. To elucidate the potential downstream target(s) regulated by Nox4, we performed a microarray screen to assess the transcriptomes of transgenic (tg) mouse hearts in which Nox4 was overexpressed. The screen revealed a significant increase in the expression of many antioxidant and detoxifying genes regulated by Nrf2 in tg compared to wild-type (wt) mouse hearts, and this finding was subsequently confirmed by Q-PCR. Expression of glutathione biosynthetic and recycling enzymes was increased in tg hearts and associated with higher levels of both GSH and the ratio of reduced:oxidised GSH, compared to wt hearts. The increases in expression of the antioxidant genes and the changes in glutathione redox effected by Nox4 were ablated in an Nrf2-null genetic background. These data therefore demonstrate that Nox4 can activate the Nrf2-regulated pathway, and suggest a potential role for Nox4 in the regulation of GSH redox in cardiomyocytes.

Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease

“…-/ -background (17). This demonstrates that, while an initial stimulus might be oxidative in nature, the response of the cell can subsequently result in an overall more reducing cellular environment.…”

“…Nrf2 is subject to activation by ROS, which act to regulate its localization, phosphorylation, and protein degradation (13). Levels of Nrf2 expression correlate with genes encoding the pentose phosphate pathway responsible for NADPH production, supporting its transcriptional control by redox-dependent mechanisms (17). We have preliminarily determined that oxidative stress precedes the development of reductive stress, but direct evidence either for this exclusive relationship or for the reciprocal relationship remains speculative.…”

“…The NADPH oxidase (NOX) family of enzymes generates endogenous ROS and has been shown to be critical mediators of oxidative signaling during cardiac remodeling (9). Moreover, we have shown that mice, which specifically overexpress NOX4 in cardiomyocytes, have been shown to activate directly Nrf2 signaling pathways and to result in the increased expression of Nrf2 target genes, especially those involved in GSH synthesis and recycling, such as GCL and GR (17). The increased ROS produced by NOX4 in this system caused a change in the intracellular GSH redox state to generate a more reduced intracellular environment (i.e., > GSH/GSSG ratio), which was ablated in an Nrf2…”

NADPH-Oxidase 4 Protects against Kidney Fibrosis during Chronic Renal Injury

“…8,19 However, NOX4 may participate to oxygen sensing and exhibit anti-inflammatory properties via regulation of the NRF2 pathway in the heart. 15,20 To determine the role of NOX4 and NOX2 in kidney fibrosis progression, we performed unilateral ureteral obstruction (UUO) on wild-type (WT), and NOX4 knockout (KO) mice as well as on NOX2 and NOX4/NOX2 KO mice. Indeed, UUO is a well described model of renal tubular stress leading to kidney fibrosis.…”

Possible Role of Nrf2 in Oxidative and Inflammatory Processes During Menopause

“…In a model overload it was found that the increased expression of Nrf2 decreased myocardial hypertrophy, cardiac fibroblasts and ROS production, the latter, most likely by modulating the activity of Nox4 [54]. Although the sharp increase in the Nrf2 content is cardioprotective, to modulate the production of ROS, apparently chronic activation may have a contrary effect called "reductive stress", so more studies on their impact is required.…”