Elsevier

Gene

Volume 498, Issue 1, 25 April 2012, Pages 107-111
Gene

Short Communication
The dual behavior of heat shock protein 70 and asymmetric dimethylarginine in relation to serum CRP levels in type 2 diabetes

https://doi.org/10.1016/j.gene.2012.01.085Get rights and content

Abstract

Background

Experimental evidence suggests that heat shock proteins (HSP) and asymmetric dimethylarginine (ADMA) are induced in the state of chronic inflammation and stress conditions. They are both inhibitors of nitric oxide synthase (NOS). The aim of this study was to evaluate the correlation between ADMA and HSP70, in patients with type 2 diabetes with respect to serum levels of C reactive protein (CRP).

Methods

We quantified serum HSP70, ADMA and CRP in 80 newly-diagnosed patients with type 2 diabetes plus 80 age-, sex and BMI-matched healthy controls. The patients and controls were also stratified into groups of high and low CRP levels (cut-point: 2.5 mg/ml).

Results

Patients with type 2 diabetes had significantly higher serum HSP70 (0.52 [0.51–0.66] vs. 0.27 [0.26–0.36], p < 0.001), ADMA (0.86 [0.81–0.92] vs. 0.72 [0.71–0.85], p < 0.05) and CRP (2.9 [1.7–3.4] vs. 1.6[1.2–2.3], p < 0.05) compared with healthy controls. Serum HSP70 and ADMA levels were significantly correlated in patients with high CRP levels (r = 0.89, p < 0.01), whereas there were no correlation in patients with low CRP (r =  0.37, p = 0.07) and controls. This correlation was significant (r = 0.77, p < 0.001) in patients with high CRP and also in patients with low CRP levels (r =  0.51, p < 0.05), after multiple adjustments for LDL and HDL levels.

Discussion

We showed that, in a state of high inflammation; serum levels of ADMA parallel the HSP70 levels. However in low inflammation, they are negatively correlated. The duality in HSP70 and ADMA correlation may be related to the duality of NOS function in low and high CRP levels.

Highlights

► We studied the correlation of HSP70and ADMA in diabetic patients and controls. ► We examine if the correlation changes in the high and low inflammation. ► HSP70 and ADMA were positively correlated in patients with high CRP. ► HSP70 and ADMA were negatively correlated in patients with low CRP. ► HSP70 and ADMA were not correlated in controls.

Introduction

Inflammation is a pathological process characterized by injury or destruction of the tissue caused by a variety of cytological and chemical reactions (Cullen et al., 2003). Most inflammatory reactions can be clinically detected by pain and swelling. However, inflammation at the molecular level may not be initially detected. This will usually happen in the atherosclerosis, coronary heart disease, type 2 diabetes and metabolic syndrome (Cullen et al., 2003, Dandona et al., 2005). Some years ago a hypothesis was proposed suggesting that elements of innate immune system, such as acute phase reactants and C reactive proteins (CRP) contribute to the development of type 2 diabetes (Crook, 2004, Dandona et al., 2005). Later on, this idea was supported by studies reporting elevated levels of inflammatory markers including white blood cell count, CRP, asymmetric dimethylarginine (ADMA) and heat shock proteins (HSP) in patients with type 2 diabetes (Nakhjavani et al., 2010a, Nakhjavani et al., 2010b, 2011).

Heat-shock proteins (HSP) or stress proteins are molecular chaperones that play an important role in protein folding, intracellular transport of proteins, and coping with proteins denatured by heat and other stressors (Ritossa, 1996). Heat-shock proteins are named according to their molecular weight (HSP70: 70 kDa in size), are highly conserved and present in all cells of all organisms (Li and Srivastava, 2004). HSPs, play crucial roles in folding/unfolding of proteins, assembly of multiprotein complexes, transport/sorting of proteins into correct subcellular compartments, cell-cycle control and signaling, and protection of cells against stress/apoptosis (Li and Srivastava, 2004, Santoro, 2000). Production of high levels of heat shock proteins can be triggered by exposure to environmental stressors such as inflammation and oxidative stress (Santoro, 2000). Consequently, heat shock proteins are also referred to as stress proteins and their up-regulation is described as a part of the stress response (Gullo and Teoh, 2004, Jacquier-Sarlin et al., 1994, Voegeli et al., 2008).

HSPs, such as HSP70, have significant cardiovascular role (Benjamin and McMillan, 1998). HSPs bind both endothelial nitric oxide syntheses (NOS) and soluble guanylate cyclase which in turn are involved in vascular relaxation (Antonova et al., 2007). Nitric oxide (NO) is a key chemical involved in normal endothelial function and, generally, cardiovascular health (Yilmaz et al., 2005). Similar to HSPs, ADMA is an inhibitor of NOS that has an important cardiovascular function (Yilmaz et al., 2005). ADMA is a plasma factor that interferes with l-arginine in production of NO (Surdacki, 2008). Raised levels of ADMA are reported to be associated with adverse consequences for cardiovascular and metabolic diseases, particularly in diabetic patients (Surdacki, 2008). Although experimental studies have shown that both HSP and ADMA are NOS inhibitors, no clinical studies have evaluated the association of these two molecules. Furthermore, experimental studies have shown that ADMA, like HSPs, is induced in the state of chronic inflammation and stress conditions (Nakhjavani et al., 2010a, Nakhjavani et al., 2010b). Therefore, it is interesting to evaluate the association of serum level of ADMA and HSP70 in a clinical setting of patients with chronic inflammation. In this study, we aimed to evaluate the association of HSP70 and ADMA, in patients with type 2 diabetes with respect to serum hs-CRP levels.

Section snippets

Methods

We performed a cross-sectional study on 80 patients with newly-diagnosed type 2 diabetes plus 80 controls. Patient's recruitment was from the diabetes clinic of Vali-Asr Hospital, affiliated with Tehran University of Medical Sciences. Diabetes was diagnosed according to the criteria of the American Diabetes Association (Pradhan et al., 2001). None of the patients and controls was on any type of anti-diabetes, anti-lipidemic, anti-hypertensive, anti-oxidant treatments at the time of the study.

Blood samples

Blood samples were collected after 12 h of fasting and were kept at − 70 °C until analysis. Serum creatinine, fasting plasma glucose (FPG), total cholesterol, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and HbA1c were measured for all participants. Glucose measurements (intra-assay coefficient of variants [CV] 2.1%, inter-assay CV 2.6%) were carried out using the glucose oxidase method. Cholesterol, HDL-C, LDL-C and TG were

Statistical analysis

The statistical package SPSS 17 for windows (Chicago, Illinois, USA), was used for analysis. Kolmogorov–Smirnov test was employed to test the normality of the variables in each group. Variables distributed normally are presented as mean ± standard error of mean (SEM). For further analysis, we stratified the patients and controls into groups of high and low hs-CRP levels (cut-point: 2.5 mg/ml) (Pepys and Hirschfield, 2003). Variables were compared between the groups using independent sample T test

Results

Demographic data of the participants are illustrated in Table 1. No differences were found in the studied variables between males and females in patients or control groups. The mean of waist, BMI, LDL-C, HDL-C, systolic blood pressure and diastolic blood pressure levels were similar between patients and controls (Table 1). Patients with type-2 diabetes had higher serum HSP70, ADMA, hs-CRP, TG, cholesterol, HbA1c, HOMA-IR and FPG levels than controls (Table 1).

We stratified the patients with

Discussion

Of all the studied biomarkers, CRP is the most promising in predicting outcome in patients with metabolic syndrome (Ridker et al., 2004). It is a nonlipid cardiovascular event risk marker, which those with high levels have an increased risk of type 2 diabetes, and death from cardiovascular disorders (Duffy and Salerno, 2004, Han et al., 2002). Serum CRP levels above 2.4 mg/l has been associated with a doubled risk of coronary events compared to levels below 1 mg/l (Pepys and Hirschfield, 2003).

Conflict of interest

The authors do not have any conflicts to declare.

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