Insulin Resistance Promotes Early Atherosclerosis via Increased Proinflammatory Proteins and Oxidative Stress in Fructose-Fed ApoE-KO Mice

Abstract

High fructose intake induces an insulin resistance state associated with metabolic syndrome (MS). The effect of vascular inflammation in this model is not completely addressed. The aim of this study was to evaluate vascular remodeling, inflammatory and oxidative stress markers, and atheroma development in high-fructose diet-induced insulin resistance of ApoE-deficient mice (ApoE-KO). Mice were fed with either a normal chow or a 10% w/v fructose (HF) in drinking water over a period of 8 weeks. Thereafter, plasma metabolic parameters, vascular remodeling, atheroma lesion size, inflammatory markers, and NAD(P)H oxidase activity in the arteries were determined. HF diet induced a marked increase in plasma glucose, insulin, and triglycerides in ApoE-KO mice, provoked vascular remodeling, enhanced expression of vascular cell-adhesion molecule-1 (VCAM-1) and matrix metalloprotease 9 (MMP-9) and enlarged atherosclerotic lesion in aortic and carotid arteries. NAD(P)H oxidase activity was enhanced by fructose intake, and this effect was attenuated by tempol, a superoxide dismutase mimetic, and losartan, an Angiotensin II receptor antagonist. Our study results show that high-fructose-induced insulin resistance promotes a proinflammatory and prooxidant state which accelerates atherosclerotic plaque formation in ApoE-KO mice.

Moderate chronic administration of Vineatrol-enriched red wines improves metabolic, oxidative, and inflammatory markers in hamsters fed a high-fat diet

“…The red wine induced insulin sensitization we observed could contribute to the reduction of oxidative stress, which is closely linked to insulin resistance [51]. It is well known that the co-existence of an insulin-resistant state and hepatic oxidative stress contributes to the development of NAFLD [52], which is increasingly considered as an independent risk factor for atherosclerosis and CVD, even if their mechanistic relationships are not yet fully understood [53].…”

Insulin resistance as a predictor of cardiovascular morbidity and end-stage renal disease

“…Several mechanisms through which impaired insulin resistance could result in atherosclerosis are pointed out in the literature: the insulin anti-aggregating platelet effect, the inhibition by insulin of migration of vascular smooth muscle cells, the effect of the hormone on nitric oxide release from the endothelium, the inhibitory effect of the hormone on fibrinogen synthesis and also the promotion of a proinflammatory and prooxidant state (Bonora et al, 2002;Cannizzo, Luján, Estrella, et al, 2012;Martínez-Hervás & Vinué, 2014).…”

Molecular Imaging of Vulnerable Atherosclerotic Plaques in Animal Models

“…One of the first mouse models of diabetic atherosclerosis was the diet-induced obese (DIO) C57Bl/6J mouse, but only 40% of these mice developed small lipid deposits in the aortic sinus after 14 weeks of a diabetogenic diet (DD, 35.5% energy from fat); therefore, this appeared to be a poor model for the study of atherosclerotic complications in diabetes [ 106 ]. The genetically modified mouse models ApoE −/− (King 2010; Canizzo 2012) [ 107 , 108 ] and LDL −/− [ 109 , 110 ] also failed as pure diet-induced diabetic atherosclerosis models, because they have exhibited inconsistent effects on blood glucose or insulin levels or on the development of insulin resistance, and the variable increment of plaques would mainly be related to hyperlipidemia rather than to alterations in glucose metabolism.…”