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Published on: February 25, 2016
Nox2 NADPH oxidase has a critical role in insulin resistance-related endothelial cell dysfunction
Piruthivi Sukumar1, Hema Viswambharan, Helen Imrie
1Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK
Abstract:
Insulin resistance is characterized by excessive endothelial cell generation of potentially cytotoxic concentrations of reactive oxygen species. We examined the role of NADPH oxidase (Nox) and specifically Nox2 isoform in superoxide generation in two complementary in vivo models of human insulin resistance (endothelial specific and whole body). Using three complementary methods to measure superoxide, we demonstrated higher levels of superoxide in insulin-resistant endothelial cells, which could be pharmacologically inhibited both acutely and chronically, using the Nox inhibitor gp91ds-tat. Similarly, insulin resistance-induced impairment of endothelial-mediated vasorelaxation could also be reversed using gp91ds-tat. siRNA-mediated knockdown of Nox2, which was specifically elevated in insulin-resistant endothelial cells, significantly reduced superoxide levels. Double transgenic mice with endothelial-specific insulin resistance and deletion of Nox2 showed reduced superoxide production and improved vascular function. This study identifies Nox2 as the central molecule in insulin resistance-mediated oxidative stress and vascular dysfunction. It also establishes pharmacological inhibition of Nox2 as a novel therapeutic target in insulin resistance-related vascular disease.
Insights
Insulin resistance causes harmful oxidative stress in blood vessels. Targeting NADPH oxidase (Nox)2, an enzyme elevated in this condition, reduces this stress and improves vascular function, offering a new therapeutic approach.
Area of Science:
- Biomedical Science
- Vascular Biology
- Metabolic Disorders
Background:
- Insulin resistance is linked to increased oxidative stress in endothelial cells.
- Reactive oxygen species (ROS) generated by NADPH oxidase (Nox) contribute to vascular dysfunction.
Purpose of the Study:
- To investigate the role of Nox enzymes, particularly Nox2, in insulin resistance-associated oxidative stress.
- To evaluate the therapeutic potential of inhibiting Nox2 in models of insulin resistance.
Main Methods:
- Utilized two in vivo models of insulin resistance (endothelial-specific and whole body).
- Employed three methods to quantify superoxide levels.
- Administered the Nox inhibitor gp91ds-tat and used siRNA for Nox2 knockdown.
- Assessed endothelial-mediated vasorelaxation.
Main Results:
- Elevated superoxide levels were observed in insulin-resistant endothelial cells.
- Pharmacological inhibition and genetic knockdown of Nox2 significantly reduced superoxide production.
- Treatment with gp91ds-tat reversed insulin resistance-induced vasorelaxation impairment.
- Mice lacking Nox2 in endothelial cells showed reduced oxidative stress and improved vascular function.
Conclusions:
- Nox2 is a key mediator of oxidative stress and vascular dysfunction in insulin resistance.
- Pharmacological inhibition of Nox2 presents a promising therapeutic strategy for vascular complications associated with insulin resistance.
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