# NADPH Oxidase 1 Mediates Endothelial Dysfunction and Hypertension in a Murine Model of Obesity

## TL;DR

This study shows that NADPH oxidase 1 (NOX1) contributes to hypertension and endothelial dysfunction in obesity, and inhibiting it may offer a new treatment.

## Contribution

The study identifies NOX1 as a key driver of endothelial dysfunction in obesity and demonstrates the therapeutic potential of NOX1 inhibition.

## Key findings

- NOX1 deletion in obese mice reduced hypertension without affecting metabolism.
- NOX1 inhibition with GKT771 restored endothelial function in obese mice.
- NOX1 deletion improved kidney sodium handling without upregulating other NOX isoforms.

## Abstract

Obesity is a foremost risk factor for the development of cardiovascular disease, a hallmark of which is chronic vascular inflammation and overproduction of reactive oxygen species (ROS). NADPH oxidases (NOX) are central mediators of ROS overproduction in the obese vasculature, yet a complete understanding of the mechanism underlying their dysregulation in obesity remains poorly understood. Herein, we investigated the contribution of NOX1 in obesity-associated hypertension and evaluated the therapeutic potential of pharmacologically targeting NOX1 using the novel inhibitor GKT771. In obese db/db mice, NOX1 deletion ameliorated hypertension independent of metabolic improvements such as weight loss or improved glucose handling. Furthermore, NOX1 deletion improved renal sodium handling with no compensatory upregulation of other NOX isoforms. Importantly, treatment with the NOX1-specific inhibitor GKT771 rescued endothelial function in obese mice, restoring microvascular function to levels observed in lean controls. These data highlight the importance of NOX1 as a driver of endothelial dysfunction in obesity and suggest that NOX1 inhibition may offer a novel therapeutic strategy for obesity-associated endothelial dysfunction and its downstream cardiovascular complications.