Whole-body insulin resistance leads to accelerated atherosclerosis: role for Nox2 NADPH oxidase

Whole-body insulin resistance leads to accelerated atherosclerosis: role for Nox2 NADPH oxidase

Insulin resistance underpins the progression of type 2 diabetes mellitus and leads to a collection of risk factors for the development of atherosclerosis. Whether or not insulin resistance at a whole-body level per se leads to accelerated atherosclerosis is unclear. To answer this question, we gener...

Full description

Saved in:
Bibliographic Details
Main Authors: Azhar Maqbool, Hema Viswambharan, Anna Skromna, Natallia Makava, Heba Shawer, Katherine Bridge, Shovkat Kadirovich Muminov, Helen Imrie, Kathryn Griffin, Stephen B Wheatcroft, Piruthivi Sukumar, Richard M Cubbon, Mark T Kearney, Nadira Yusupovna Yuldasheva
Format: Article
Language:English
Published: Bioscientifica 2024-11-01
Series:Vascular Biology
Subjects:
atherosclerosis
insulin resistance
nox2 nadph oxidase
Online Access:https://vb.bioscientifica.com/view/journals/vb/6/1/VB-23-0018.xml
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Insulin resistance underpins the progression of type 2 diabetes mellitus and leads to a collection of risk factors for the development of atherosclerosis. Whether or not insulin resistance at a whole-body level per se leads to accelerated atherosclerosis is unclear. To answer this question, we generated atherosclerosis-prone mice with whole-body insulin resistance secondary to haploinsufficiency of the insulin receptor (IR+/−) deficient in ApoE−/− (IR+/−/ApoE−/−). IR+/−/ ApoE−/− and ApoE−/− littermates had similar weight, lipids, and glucose tolerance at baseline. After 12 weeks of Western high-cholesterol diet, IR+/−/ApoE−/− had significantly more atherosclerosis in the thoracoabdominal aorta and at the level of the aortic sinus than ApoE−/− littermates. Excess Nox2 NADPH oxidase (Nox2) derived superoxide has been suggested to underpin diabetes-related atherosclerosis. In IR+/−/ApoE−/− we examined the effect of inhibiting Nox2 using genetic or pharmacological approaches on the development of atherosclerosis. To genetically delete Nox2, we generated IR+/−/ApoE−/−/Nox2−/y and to inhibit Nox2 pharmacologically, we treated IR+/−/ApoE−/− with the peptide Nox2 inhibitor gp91dstat. IR+/−/ApoE−/−/Nox2−/y had significant disruption of the aortic wall with increased thoracoabdominal atherosclerosis when compared to IR+/−/ApoE−/−/Nox2+/y littermates. Inhibition of Nox2 using gp91dstat reduced atherosclerosis in the thoracoabdominal aorta of IR+/−/ApoE−/−. Whole-body insulin resistance accelerates the development of atherosclerosis. Genetic inhibition of Nox2 leads to disruption of the aortic wall in IR+/−/ApoE−/− mice with accelerated atherosclerosis, whereas pharmacological Nox2 inhibition reduces atherosclerosis in IR+/−/ApoE−/− without disruption of the arterial wall.
ISSN:2516-5658

Similar Items