Oxidative stress and dysregulation of NAD(P)H oxidase and antioxidant enzymes in diet-induced metabolic syndrome
Introduction
Metabolic syndrome, otherwise known as syndrome X or insulin resistance syndrome, is defined by the presence of insulin resistance, hyperinsulinemia, and some combination of obesity, dyslipidemia, inflammation, endothelial dysfunction, and hypertension [1], [2], [3], [4], [5], [6], [7], [8], [9]. The incidence of metabolic syndrome has reached epidemic proportion worldwide due primarily to prevailing sedentary lifestyle and unhealthy dietary habits. Consequently, metabolic syndrome has emerged as a major cause of diabetes, cardiovascular, and kidney diseases in the industrialized societies [10], [11].
In a series of earlier studies, we demonstrated that chronic consumption of a high-fat, high-refined sugar (HFS) diet induces obesity, insulin resistance, dyslipidemia, and hypertension in genetically normal rats [12], [13]. Hypertension in this model is associated with oxidative stress [14], avid nitric oxide (NO) inactivation, depressed NO bioavailability [15], and downregulations of NO synthase (NOS) isoforms, AKT (eNOS activator), and soluble guanylate cyclase (downstream target of NO) [14]. It is of note that diminished NO production and NOS expression found in rats with diet-induced metabolic syndrome are also seen in the obese Zucker rats with hereditary metabolic syndrome [16]. The reduced NO production capacity in the obese Zucker rats is associated with inflammation and activation of inflammatory pathways [17].
Oxidative stress plays a major role in the pathogenesis of endothelial dysfunction, hypertension, inflammation, and atherosclerotic cardiovascular disease. Although the presence of oxidative stress and its impact on NO metabolism in rats with diet-induced metabolic syndrome are well established [14], [15], the molecular sources of the reactive oxygen species (ROS) in this model are uncertain. Oxidative stress can result from either excess ROS production and/or deficient antioxidant capacity. The present study was designed to test the hypothesis that oxidative stress in rats with diet-induced metabolic syndrome may be due to upregulation of NAD(P)H oxidase (a major source of ROS in the kidney and cardiovascular tissues) and downregulation of the main antioxidant enzymes, superoxide dismutases, glutathione peroxidase (GPX), catalase (CAT), and heme oxygenase.
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Animals and diets
All protocols were approved and conducted in accordance with the University of California, Los Angeles, Animal Research Committee. Two-month-old female Fischer 344 rats were obtained from Harlan Sprague Dawley (San Diego, Calif). We have used this rat model in previous studies, as the female Fischer rat normally shows little weight gain after the maturation phase [12], [18]. The animals (6 per group) were housed in a light-controlled (12-hour light cycle starting at 7 am) and
Blood pressure and MDA
Tail arterial blood pressure at the conclusion of the 7-month study period was slightly higher in the HFS group (131 ± 6 mm Hg) than in the LFCC group (120 ± 2 mm Hg, P > .05). Likewise, plasma MDA level in the HFS group (1.91 ± 0.08 μmol/L) was significantly greater than in the LFCC group (1.37 ± 0.06 μmol/L, P < .05) denoting the presence of oxidative stress in the HFS rats.
NAD(P)H oxidase
Data are illustrated in Fig. 1. The gp91phox protein abundance in the thoracic aorta was significantly greater in the
Discussion
Several studies have shown that diets high in fat and refined sugars (sucrose or fructose) cause endothelial dysfunction and ultimately hypertension [15], [22], [23], [24], [25]. Endothelial dysfunction and hypertension in these and other models are associated with and, at least in part, due to oxidative stress [26], [27]. Oxidative stress in the kidney and vascular tissues can promote endothelial dysfunction by several mechanisms. For instance, oxidative stress limits the bioavailability of NO
Acknowledgment
Christian Roberts was supported by a National Research Scholarship Award postdoctoral fellowship (NIH F32 HL68406-01) during this project.
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