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

Autor:	Maqbool A; A Maqbool, Leeds, United Kingdom of Great Britain and Northern Ireland., Viswambharan H; H Viswambharan, Leeds, United Kingdom of Great Britain and Northern Ireland., Skromna A; A Skromna, Leeds, United Kingdom of Great Britain and Northern Ireland., Makava N; N Makava, Leeds, United Kingdom of Great Britain and Northern Ireland., Shawer H; H Shawer, The Nuffield Department of Medicine (NDM), University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, United Kingdom of Great Britain and Northern Ireland., Bridge K; K Bridge, Leeds, United Kingdom of Great Britain and Northern Ireland., Muminov SK; S Muminov, Tashkent Pediatric Medical Institute, Tashkent, Uzbekistan., Imrie H; H Imrie, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom of Great Britain and Northern Ireland., Griffin K; K Griffin, University of Leeds Faculty of Medicine and Health, Leeds, United Kingdom of Great Britain and Northern Ireland., Wheatcroft SB; S Wheatcroft, University of Leeds Faculty of Medicine and Health, Leeds, United Kingdom of Great Britain and Northern Ireland., Sukumar P; P Sukumar, University of Leeds Faculty of Medicine and Health, Leeds, United Kingdom of Great Britain and Northern Ireland., Cubbon RM; R Cubbon, University of Leeds Faculty of Medicine and Health, Leeds, United Kingdom of Great Britain and Northern Ireland., Kearney MT; M Kearney, University of Leeds Faculty of Medicine and Health, Leeds, United Kingdom of Great Britain and Northern Ireland., Yuldasheva NY; N Yuldasheva, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds Faculty of Medicine and Health, Leeds, LS2 9JT, United Kingdom of Great Britain and Northern Ireland.
Jazyk:	angličtina
Zdroj:	Vascular biology (Bristol, England) [Vasc Biol] 2024 Oct 01. Date of Electronic Publication: 2024 Oct 01.
DOI:	10.1530/VB-23-0018
Abstrakt:	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 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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu