7Các quy định của EC-SOD trong tế bào mỡ HypoxicTetsuro Kamiya1, 2, Hirokazu Hara1, điện Inagaki2 và Tetsuo Adachi11Gifu dược phẩm đại học,Đại học 2GifuNhật bảnGiới thiệuObesity is closely linked to a variety of metabolic disorders, including insulin resistance, atherosclerosis and type 2 diabetes (Eriksson, 2007). Recent studies have indicated that adipose tissue is not only an energy store but also produces and secretes various bioactive molecules called adipocytokines, such as adiponectin, tumor necrosis factor-a (TNF-a), plasminogen activator inhibitor type 1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1) (Hotamisligil & Spiegelman, 1994; Shimomura et al., 1996; Berg et al., 2002; Havel, 2004). TNF-a is a major inflammatory adipocytokine that decreases the phosphorylation of insulin receptor substrate-1 (IRS-1), and this event leads to insulin resistance (Hotamisligil et al., 1993). Moreover, because it is well recognized that TNF-a increases the adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and MCP-1, all of which are key mediators involved in atherogenesis, over secretion of TNF-a may induce and accelerate atherosclerosis. On the other hand, adiponectin is a major anti-inflammatory adipocytokine that plays a pivotal role in the improvement of glucose and lipid metabolism and the prevention of atherosclerosis and inflammation (Yamauchi et al., 2002). Further, it has been clarified that adiponectin not only increases insulin sensitivity, but also has anti-atherosclerosis properties which decrease the expression of VCAM-1 and ICAM-1 (Ouchi et al., 1999) and suppresses the proliferation of vascular smooth muscle cells (Arita et al., 2002). In patients with insulin resistance, obesity or type 2 diabetes, serum adiponectin levels are reduced (Arita et al., 1999; Hotta et al., 2000). Further, previous studies showed that TNF-a and intracellular reactive oxygen species (ROS) decrease adiponectin expression (Kim et al., 2005; Soares et al., 2005; Simons et al., 2007). On the other hand, increases in adiponectin expression have been reported during adipocyte differentiation and transcriptional factors associated with adipogenesis, including CCAAT/enhancer-binding protein-a (C/EBP-a) and peroxisome proliferator- activated receptor-g (PPAR-g), have been shown to up-regulate adiponectin expression (Adachi et al., 2009).Adipose tissue has been found to suffer chronic hypoxia during the development of obesity (Brook et al., 1972; Helmlinger et al., 1997), and these conditions may lead to metabolic disorders. Hypoxic conditions can be induced by the addition of certain chemicals called ‘hypoxia mimetics’, such as the carcinogenic transition metal cobalt (Vincent et al., 1996). It144 Medicinal Chemistry and Drug Designhas been suggested that cobalt stabilizes transcriptional factor, hypoxia-inducible factor-1a (HIF-1a), from proteasomal degradation by inhibiting the activity of prolyl hydroxylases (PHDs) through Fe2+ substitution (Schofield & Ratcliffe, 2004). In these hypoxic conditions, it has been recognized that accumulated HIF-1a increases a wide variety of genes including vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), erythropoietin (EPO) and cytochrome p450 (CYP) 3A6 to ensure adaptation to low-oxygen tension (Levy et al., 1995; Lee et al., 1997). On the other hand, the expression of CYP1A2, 2B and 2C are decreased by the activation of HIF-1a (Olsvik et al., 2006; Fradette et al., 2007). Further, it has been reported that both hypoxia and hypoxia mimetics increase ROS generation and dysregulate adipocytokines, and these conditions lead to and/or promote metabolic disorders (Schuster et al., 1989; Hosogai et al., 2007).To protect cells from oxidative stress, mammalian have anti-oxidative enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase (Amstad & Cerutti, 1990; Cerutti et al., 1994). SOD is a major antioxidant enzyme that protects cells from the damaging effects of superoxide by accelerating the dismutation reaction of superoxide by approximately 10,000 times (Faraci, 2003). As shown in Table 1, there are three SOD isozymes in mammals; copper and zinc-containing SOD (Cu,Zn-SOD), manganese- containing SOD (Mn-SOD) and extracellular-SOD (EC-SOD) (McCord & Fridovich, 1969; Keele et al., 1970; Marklund, 1982; Faraci, 2003). Among of three SOD isozymes, EC-SOD is secretory, tetrameric glycoprotein, whereas Cu,Zn-SOD and Mn-SOD are intracellular enzymes found predominantly in the cytoplasm and mitochondria, respectively. EC-SOD is a major SOD isozyme in the extracellular space but is distributed mainly in blood vessel walls (Ookawara et al., 1998). After secretion, EC-SOD slowly diffuses and binds to the heparan sulfate proteoglycans in the glycocalyx on the surface of most cell types in the vascular wall. The EC-SOD content is very low in the liver, heart, brain and other organs, with the exception of the lung, thyroid gland, and adipose tissue (Marklund, 1984). It was found that the plasma EC-SOD levels in type 2 diabetic patients were significantly and inversely related to the body mass index, homeostasis model assessment-insulin resistance index, but positively related to adiponectin levels (Adachi et al., 2004). Recently, we reported that cobalt chloride (CoCl2) decreases EC-SOD in green monkey kidney COS7 cells via intracellular ROS generation and p38-MAPK, a mitogen-activated protein kinase
đang được dịch, vui lòng đợi..