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

Azhar MaqboolLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKHema ViswambharanLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKAnna SkromnaLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKNatallia MakavaLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKHeba ShawerThe Welcome Trust Centre for Human Genetics, University of Oxford, UKKatherine BridgeLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKShovkat Kadirovich MuminovTashkent Pediatric Medical Institute, Tashkent, UzbekistanHelen ImrieThe Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UKKathryn J GriffinLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKStephen B. WheatcroftLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKPiruthivi SukumarLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKRichard M. CubbonLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKMark T. KearneyLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UKN YuldashevaLeeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds, UK

Vascular Biologyjournal2024en

ABI

Annotatsiya

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.

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Mavzular

Atherosclerosis and Cardiovascular Diseases Neutrophil, Myeloperoxidase and Oxidative Mechanisms Nitric Oxide and Endothelin Effects

Identifikatorlar

DOI: 10.1530/vb-23-0018

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