Nadph Oxidase Activation and Oxidative Stress in High-Fat Diet-Induced Hypertension and Metabolic Disorders

Abstract

Dietary obesity is a major risk factor for the development of cardiovascular diseases. However, the mechanism of high fat diet (HFD)-induced vascular dysfunction remains unclear. In this study we investigated the role of a Nox2-containing NADPH oxidase in high fat diet (HFD: 45% kcal fat)-induced metabolic disorders using Nox2/ApoE double knockout mice in comparison to age-matched ApoE−/− mice on the C57BL/6 background (n=9). ApoE−/− mice under 10 weeks of HFD had significant increases in body weight (NCD 27.9±1.5 vs HFD 31.3±1.1 g) and blood pressure (NCD 114±3.6 vs HFD 128.5±5.7 mm Hg) together with hyperglycaemia and hyperinsulinaemia as compared to age-matched littermates under a normal chow diet (NCD: 9.3% kcal fat). Aortas from HFD ApoE−/− mice had significant increases in O2.-production as detected by lucigenin-chemiluminescence and DHE fluorescence, and this was accompanied by increased endothelium Nox2 expression, Akt and ERK1/2 phosphorylation (immunofluorescence) and impaired endothelium function as assessed by an aorta organ bath. However, all these HFD-induced abnormalities were absent in Nox2/ApoE double knockout mice under the same HFD. Ex vivo organ culture (24 h) further confirmed that high levels of glucose (30 mM) plus insulin (1.2 nM) caused damages to ApoE−/− vessels (but not to vessels from Nox2/ApoE double knockout mice) characterised by ERK1/2 activation, reduced insulin receptor expression and deterioration of endothelial function. In conclusion, Nox2-derived oxidative stress plays an important role in the pathogenesis of dietary obesity-associated metabolic syndrome and endothelial dysfunction. Targeting Nox2-derived ROS represents a valuable therapeutic strategy to these diseases.

Nox2 dependent redox-regulation of Akt and ERK1/2 to promote left ventricular hypertrophy in dietary obesity of mice

“…Nox2-derived ROS production caused by excessive glucose and insulin challenge also elicits ERK1/2 activation, resulting in endothelial cell injury, dysfunction and death [30]. Studies report that Nox2 augments endothelial p-ERK1/2 expression after chronic HFD feeding [7,11]. Our findings strongly suggest a contribution of myocardial Nox2 in HFD-induced ERK1/2 activation.…”

“…HFD feeding reduces insulin sensitivity as early as five days of intervention [9], associates with oxidative stress and promotes vascular damage involving cardiac remodelling, hypertrophy and apoptosis [10]. Aortic Nox2 overexpression occurs in HFD-fed ApoE knockout mice in unison with increased activation of both Akt and ERK1/2 and is associated with endothelial dysfunction [11]. Moreover, it has been reported that caloric restriction reverses endothelial oxidative damage in these conditions [12].…”

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“…Findings reveal that individuals with hyperlipidaemia produce more reactive oxygen species (ROS) 10 . This could be due to a fat-rich diet increasing the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase genes 11 , which is the primary enzyme responsible for ROS synthesis 12 resulting in increased ROS formation in cells 13 . Low-density lipoprotein (LDL) oxidation is triggered by the presence of ROS, which activates inflammatory cytokines, mediators and chemokines produced by invading resident macrophages.…”