Divergence of intracellular and extracellular HSP72 in type 2 diabetes: does fat matter?

Autor: Giuseppe De Vito, Gerard Colleran, Ciara O'Hagan, Josianne Rodrigues-Krause, Mauricio Krause, Colin Boreham, Colin Murphy, Philip Newsholme
Rok vydání: 2012
Předmět:
Zdroj: Cell Stress and Chaperones. 17:293-302
ISSN: 1466-1268
1355-8145
DOI: 10.1007/s12192-011-0319-x
Popis: Mammalian cells have developed a range of adaptations to survive against acute and prolonged (but not lethal) stresses (Beckmann et al. 1992). Among these adaptations, the heat shock response is the most conserved, being found in all prokaryotes and eukaryotes (Locke and Noble 1995). Heat shock proteins (HSPs) are considered part of a family of proteins known as “stress proteins” since their expression is induced by a wide range of stressors, such as oxidative stress (Krause et al. 2007), thermal stress (Yang et al. 1996), ischaemia (Richard et al. 1996), exercise (Krause et al. 2007), metabolic stress (Beckmann et al. 1992) and many others. The genes encoding Hsps are highly conserved, and many of these genes and their protein products can be assigned to different families on the basis of their typical molecular weight (kDa): HSP110 (or officially named HSPH), HSP90 (or HSPC), HSP70 (or HSPA), HSP60 (or HSPD1), HSP40 (or DNAJ) and small hsp families (HSPB) (Kampinga et al. 2009). In eukaryotes, many families comprise multiple members that differ in inducibility, intracellular localization and function (Feder and Hofmann 1999). HSP72 (or HSPA1A) is the inducible and the most abundant of all HSPs, accounting for 1–2% of cellular protein and being rapidly induced during cell stress (Noble et al. 2008), especially in the skeletal muscle cells (Madden et al. 2008). As molecular chaperones, the intracellular HSP70 protein (iHSP72) can interact with other proteins (unfolded, in non-native state and/or stress-denatured conformations) to avoid inappropriate interactions, formation of protein aggregates and degradation of damaged proteins, as well as helping the correct refolding of proteins (Madden et al. 2008). Other HSP functions include protein translocation (Chirico et al. 1988), anti-apoptosis (Garrido et al. 2001) and anti-inflammatory responses (Homem de Bittencourt et al. 2007). The anti-inflammatory role of the iHSP72 is mediated by its interaction with the proteins involved in the activation of the nuclear factor κ-B (NF-κB), blocking its translocation to the nucleus and inducing the cessation of the inflammatory process (Homem de Bittencourt et al. 2007; Silveira et al. 2007). More recently, the HSP roles have been expanded to include control of cell signalling (Calderwood et al. 2007), modulation of immune response (Johnson and Fleshner 2006) and for chronic diseases conditions (Kampinga et al. 2007), such as diabetes, control of obesity and insulin resistance (Chung et al. 2008; Krause and Rodrigues-Krause Jda 2011). Recent data has indicated that a lack of iHSP72 response to stress can be linked to the levels of insulin resistance in skeletal muscle cells (Chung et al. 2008; Kurucz et al. 2002). Patients with T2DM have been shown to have reduced iHSP72 gene expression, which has been correlated with reduced insulin sensitivity (Kurucz et al. 2002). Furthermore, earlier studies in patients with T2DM reported that hot tub therapy improved glycaemic control (Bernstein 2000; Bathaie et al. 2010; Hooper 1999), additionally showing an inverse correlation between iHSP72 messenger RNA (mRNA) expression and the degree of T2DM (Kurucz et al. 2002). The underlying mechanisms behind the lower induction of iHSP72 expression in diabetic patients is not fully understood, but appears to be connected to the activation of proteins involved on inflammatory response (and sensitive to changes in redox state), such as the c-jun amino terminal kinase (JNK), the inhibitor of IκB (IKK), the tumor necrosis factor alpha (TNF-α) and nuclear factor kappa b (NF-κB) (Chung et al. 2008). Activation of these proteins appears to inhibit the major inductor of HSP72, the heat shock factor 1 (HSF-1), leading to a low iHSP72 expression and induction of the stress response (Chung et al. 2008). Currently, several HSP-inducing drugs are under investigation or in clinical trials for diabetic neuropathy, neurodegenerative diseases (Westerheide and Morimoto 2005; Kurthy et al. 2002) and for the prevention of insulin resistance and treatment of impaired glycaemic control (Kurucz et al. 2002; Gupte et al. 2009a; Literati-Nagy et al. 2009; Vitai et al. 2009; Kavanagh et al. 2009). Considering that skeletal muscle is the major tissue responsible for whole body insulin-mediated glucose uptake, disturbances in skeletal muscle, such as oxidative stress and inflammatory processes, can easily progress to insulin resistance and diabetes (Newsholme et al. 2009). Physical exercise is a known inducer of glucose uptake and is also a substantial inductor of iHSP72 expression (Krause et al. 2007). This may explain, in part, the beneficial effects of exercise in diabetic patients. Therefore, strategies to increase skeletal muscle iHSP72 expression (or over-expression) could result in improved glycaemic control, reduced insulin resistance and avoidance of T2DM. Heat shock proteins were long thought to be exclusive cytoplasmic proteins with functions restricted to the intracellular compartment. However, an increasing number of observations have shown that they may be released into the extracellular space (eHSP72) and have a wide variety of effects on other cells (Tytell 2005). The eHSP72 function is in general associated with the activation of the immune system (Whitham and Fortes 2008). For example, eHSP72 has been reported as an inductor of neutrophils microbicidal capacity (Ortega et al. 2006) and chemotaxis (Ortega et al. 2009), recruitment of NK (natural killer) cells (Horn et al. 2007) as well as cytokine production in immune cells (Asea et al. 2000; Johnson and Fleshner 2006). Besides that, eHSP72 was recently shown to be involved in the inducement of neural cell protection under stress conditions (Krause and Rodrigues-Krause Jda 2011). In addition, hyperglycaemia is known to be involved in inflammation and vascular complications associated with diabetes, arising from reactive oxygen species generation and action (Wei et al. 2009; Wright et al. 2006). As oxidative stress is a powerful inductor of iHSP72 (Krause et al. 2007), it is expected that during inflammatory and oxidative stress states in diabetes, the levels of these proteins in the extracellular medium (plasma and serum) may be higher in diabetic than non-diabetic participants. Indeed, type 1 (Oglesbee et al. 2005) and T2DM patients have higher levels of eHSP72, and this response has been related to the duration of the disease (Nakhjavani et al. 2010). In addition, serum eHSP72 concentrations are positively correlated with markers of inflammation, such as C-reactive proteins, monocyte count, and TNF-α (Mayer and Bukau 2005; Njemini et al. 2004). In summary, while intracellular levels of iHSP72 are decreased in T2DM and correlated with insulin resistance, extracellular eHSP72 levels are increased and correlated with oxidative damage and stress. To date, no study has investigated both intracellular and extracellular levels of HSP72 in T2DM patients simultaneously. Herein, we aimed to determine the levels of HSP72, intracellularly (skeletal muscle) and extracellularly (blood plasma) in three groups of patients: obese without T2DM and obese with T2DM and non-obese with T2DM. We also determined HSF-1 skeletal muscle expression for all groups.
Databáze: OpenAIRE
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