Cellular detoxification is an important process that helps r

Cellular detoxification is an important process that helps remove excess oxidants from the cellular environment through endogenous antioxidants or other molecules capable of reduction. One of the key regulators of antioxidant production is the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which regulates the production of Cepharanthine australia responsible for cellular detoxification among other functions [13]. Nrf2 controls production of several antioxidants such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), which together aid in neutralizing excess oxidant production [35]. In order for Nrf2 to translocate to the nucleus, it must dissociate from Kelch-like ECH-associated protein 1 (Keap1) in the cytosol usually by oxidation of Keap1's thiols [7].
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Discussion Some metabolic syndrome features include impaired insulin signaling (insulin resistance), elevated systolic blood pressure, dyslipidemia, and increased adiposity [6,18]. The factors contributing to the development of insulin resistance are not well known nor is the impact that insulin resistance has on mitochondrial function. However, the inappropriate activation of AT1 has been implicated as a contributor to insulin resistance and mitochondrial dysfunction making it a primary target for study. Furthermore, individuals afflicted with insulin resistance undergo multiple daily bouts of hyperglycemia because of impaired glucose uptake, which may cause cellular damage via oxidant generation from a variety of sources [10]. The aim of this study was to determine the impact of ARB treatment on mitochondrial function and antioxidant activity in the hearts of insulin resistant rats. We found that chronic blockade of AT1 protects and stabilizes mitochondrial enzyme activity in the hearts of insulin resistant rats during an acute glucose challenge. Inappropriate AT1 activation is a known consequence of metabolic syndrome and increases p47phox translocation, which initiates the assemblage of NADPH oxidase [8,21]. Exposure to an acute glucose challenge increased p47phox translocation over two hours in OLETF rats, while translocation was stabilized in LETO and ARB with levels decreasing in both groups at the 2-h time point. This indicates that insulin resistance is associated with susceptibility of the heart to abrupt increases in glucose-mediated oxidant production through p47phox translocation which has been implicated in diabetic nephropathy and vascular disease [15,17]. The ability of chronic AT1 blockade to ameliorate the glucose-induced increase in translocation suggests that this glucose effect is partially AT1 mediated. Keap1 facilitates degradation of Nrf2 through a Cul3 ring-box ligase [12] and is susceptible to oxidation on its cysteine switches. Oxidation of Keap1 causes liberation of Nrf2 and subsequent translocation in the nucleus. Nrf2, free of Keap1, can regulate phase II gene transcription by binding to the EpRE [26]. Thus, lower Keap1 levels may be indicative of a greater potential of Nrf2 to induced phase II gene transcription, including CAT, GPx, and SOD [29,35]. The lower Keap1 protein levels in ARB after 6 wks of treatment suggests that the ability of ARB to ameliorate the insulin resistance-associated oxidative damage observed in OLETF rats and other models of diabetes and metabolic syndrome may be achieved by decreasing cytosolic Keap1. Glucose infusion tended to increase Keap1 protein levels in LETO and OLETF over the 2h; however, levels remained similarly suppressed in ARB at the first measurement hour suggesting that chronic blockade of AT1 protects the heart from any potential glucose-induced increases. Keap1 levels in ARB increased at T120 suggesting that chronic blockade of AT1 desensitizes the heart from abrupt increases in plasma glucose and delays the onset of increasing Keap1. The lack of robust changes in Keap1 protein in LETO and OLETF was associated with similarly unaltered Nrf2 binding to the EpRE. Conversely, the reduced Keap1 levels in ARB were associated with profoundly increased Nrf2 binding, corroborating the impact of AT1 signaling in the Keap1-Nrf2 pathway. Similarly, the increasing trend in Keap1 was associated with decreased Nrf2 binding at T120 in the LETO and OLETF groups. This is important because it demonstrates that Nrf2 activity is not impaired in the early stages of insulin resistance and is not diminished by acutely elevated glucose. This increase in binding is associated with the relative amount of Nrf2 in the nucleus at the respective time points [20].