Correlation between E3 SUMO-Protein Ligase NSE2 (NSMCE2) with 5'-nucleotidase, XOR, uric acid and total protein in patients with atherosclerosis.
Major clinical manifestations of Cardiovascular disease (CVD) include myocardial infarction, coronary artery disease, stroke and peripheral artery disease. In most cases, these clinical conditions result from atherosclerosis., "as discussed by Cervelli (2012)". Atherosclerosis is a continuum of lesions resulting from the deposition of cholesterol in the arterial wall, favored by circulating oxidized LDL cholesterol. In turn, cholesterol deposition triggers an inflammatory reaction resulting in arterial wall thickening and luminal narrowing or total occlusion. Atherosclerosis may be chronic, by gradually increasing cholesterol and inflammatory cells deposits, smooth muscle proliferation, and fibrosis, or acute (thrombosis on the surface of a fissured or ruptured plaque) "as discussed by Adelmann (2011)".
Small Ubiquitin-like Modifier (SUMO) proteins are a family of small proteins belongs to the ubiquitin (Ub) and ubiquitin-like (Ubl) protein family "as discussed elsewhere [3, 4]". The SUMO proteins are small; most are around 100 amino acids in length and 12 kDa in mass. The exact length and mass varies between SUMO family members and depends on which organism the protein comes from, Sumo shares only 18% sequence homology with ubiquitin "as discussed elsewhere (Alegre, K., 2013; Gao, C., 2014; Le, N.T., 2012)". SUMO proteins are covalently attaches to certain lysine residues of specific target proteins in cells and alters a number of different functions depending on the substrates "as discussed by Alegre (2013)". The SUMOylation is a dynamic and reversible process regulated by both conjugation and de-conjugation enzymes via a three-step process and three enzyme reactions, E1 (SUMO-activation enzyme) (activation), E2 (SUMO conjugation enzyme) (conjugation), and E3 (SUMO ligase) (ligation). SUMOylation is a part of important regulatory mechanisms that modify proteins in the nucleus and regulate multiple cellular processes such as nucleo-cytoplasmic signal transduction, apoptosis, stress responses, protein stability, subcellular localization of proteins, protein-protein interactions, protein-DNA interactions, and transcriptional activity of transcription factors and progression through the cell cycle "as discussed elsewhere (Le, N.T., 2012; Park, H.J., 2013)".
5'-nucleotidase is an intrinsic membrane glycoprotein, present as an ectoenzyme in a wide variety of mammalian cells and it hydrolyzes extracellular AMP to adenosine and represents the major control point for extracellular adenosine levels and is a regulator of the adenosine signaling pathway. Extracellular and intracellular 5'-nucleotidase activities regulate the quantity of nucleotides generated from both de novo and salvage pathways and participate in purine salvage to support balanced synthesis of nucleotides, which is critical for maintaining high fidelity DNA replication "as discussed elsewhere (Sowa, N.A., 2010; Augusto, E., 2013)".
Xanthine Oxidoreductase (XOR) is a rate-limiting enzyme of the purine degradation pathway, oxidizing hypoxanthine into xanthine and xanthine into uric acid. XOR has been the subject of extensive biochemical characterization as the prototypical member of the family of molybdo-flavoenzymes that consist of two identical subunits of approximately 145 kDa. XOR also serves as an important biological source of oxygen-derived free radicals "as discussed elsewhere (Boueiz, A., 2008; Patel, P.D. and R.R. Arora, 2008)". Because of its ability to generate reactive oxygen species (ROS), XOR has been thoroughly investigated in diseases where oxidative stress prevails that contribute to oxidative damage to living tissues involved in many pathological processes such as inflammation, atherosclerosis, cancer and aging. XOR is widely distributed throughout various organs including the liver, gut, lung, kidney, heart, and brain as well as the plasma and a recent study revealed microvascular endothelial cells to be rich in XOR activity "as discussed elsewhere (Sowndhararajan, K., 2012; Bhattacharya, S., 2011)". Uric acid is the end product of purine metabolism in human. XOR is responsible for the final oxidation of xanthine to uric acid "as discussed by Kamble (2011)". Coronary artery disease status can be assessed via individual and/or combinatorial protein changes in serum that assess multiple pathways of atherosclerosis "as discussed by Laframboise (2012)". The aim of the present study is to determine the level of the E3 SUMO-Protein Ligase (NSMCE2) in pg/ml and their relationship to 5'-nucleotidase and XOR enzymes U/l and some biochemical parameters including Uric acid, Total protein (Albumin, Globulin and Alb/Glb ratio) in Patients with Atherosclerosis compared with healthy normal.
MATERIAL AND METHODS
This study was conducted on a cohort of 60 patients with atherosclerosis and 30 healthy persons to be used as control ranging between (40-75) years. These patients were hospitalized at Research Institute for educational laboratories in the city of Medicine of the Ministry of Health. Five milliliter of blood sample were collected and centrifuged at [3000 rpm] for 5 min. The resultant serum were separated and stored at [-20] C until used. The NSMCE2 assay employs the quantitative sandwich enzyme immunoassay technique by CUSOBIO kit.
5'-nucleotidase activity was measured in serum according to Wood and Williams's method "as discussed by Wood (1981)". Xanthine Oxidoreductase activity in sera was determined by the method of Ackermann and Brill "as discussed by Ackermann (1974)" and Serum uric acid level was measured by enzymatic end point method supplied by Spinreact. The total serum protein concentration was determined by following Lowry's method "as discussed by Lowry (1951)", using bovine serum albumin (BSA) as a standard protein, Serum Albumin was measured by Human kit (Germany) and Electrophoresis on polyacrylamide gel containing protein as substrate was carried out on serum samples of patients and control groups "as discussed by Shi (1998)".
The present study included sixty male patients with atherosclerosis and thirty males matched apparently healthy individuals as control group. The present study showed that mean levels of sera NSMCE2 have a highly significantly increase (p<0.0001) in patients group compared to control group as shown in Table (1) and Figure (1).
The activity and specific activity of serum ecto-5'-nucleotidase showed a highly significant increase (p<0.001) in patients group compared to control group as shown in Table(2) and Figure (2).
Activity and specific activity of serum XOR showed a highly significant increase (p<0.001) in patients group compared to control group as shown in Table (3) and Figure (3).
Table (4) and Figure (4), showed a significant (p<0.05) difference in mean serum uric acid (0.42 [+ or -] 0.06) mmol/l in atherosclerosis patients than in control group (0.31 [+ or -] 0.03) mmol/l.
The mean levels of total serum protein, albumin and Alb/Glb ratio showed a significant decrease in patients group when compared to control group (p<0.05, p<0.01 and p<0.01), while globulin showed a significant increase (p<0.05) in patients group compared to control group as shown in Table (5) and Figure (5).
The presence of protein in the samples were detected and confirmed by using CBB R-250 stain as shown in Figure (6) and the gel was stained for glycoproteins by schiff's reagent as shown in Figure (7).
The SUMO covalent linkage is usually through the lysine residue(s). Some sumoylation assays revealed that in the presence of E1 and E2, the E3 ligase was dispensable to accomplish SUMO conjugation. However, SUMO E3 ligases contributed to the efficiency and specificity of SUMO conjugation and were attributed to the RING domain, which is similar to the corresponding structure in E3 ligases involved in the ubiquitination. Several reports refer that SUMO modification activated several cardiac muscle-restricted genes "as discussed elsewhere (Wang, J., 2007; Srikumar, T., 2013)". Post-translational modification by small ubiquitin-like modifier (SUMO) conjugation is achieved through a pathway that involves three steps: activation (E1), conjugation (E2) and ligation (E3). The SUMO modification of proteins has been suggested to regulate many physiological processes, such as transcriptional regulation, stress responses and protein localization. Recent studies indicate a role for sumoylation in the regulation of inflammation. Inflammation is initiated in response to tissue damage and infectious agents. Inflammatory responses must be regulated properly, and unrestricted inflammation can lead to inflammatory disorders "as discussed by Liu (2008)". Atherosclerosis is considered to be a chronic inflammatory disease "as discussed by Zemecke (2010)". The transcriptional induction of genes involved in inflammatory responses is controlled by various transcription factors, including nuclear factor [kappa]B (NF-[kappa]B), signal transducer and activator of transcription (STAT) and activator protein-1 (AP-1).
Sumoylation can regulate inflammation through the direct modulation of the activity of key transcription factors involved in inflammatory responses "as discussed elsewhere (Pascual, G., 2005; Ghisletti, S., 2007)". A member of the protein inhibitor of activated STAT (PIAS) family, PIAS1, which possesses SUMO E3 ligase activity "as discussed by Shuai (2005)", is a transcriptional repressor of NF-[kappa]B and STAT1. PIAS1 functions by blocking the DNA-binding activity of NF-[kappa]B and STAT1 on gene promoters. Recent studies indicate that PIAS1 is activated by phosphorylation in response to pro inflammatory stimuli, a process that requires the SUMO ligase activity of PIAS1. Activated PIAS1 is then recruited to inflammatory gene promoters to repress NF-[kappa]B and STAT1-mediated transcription. These findings support a hypothesis that targeting the PIAS1 sumoylation pathway might represent a novel therapeutic strategy for the treatment of inflammatory disorders such as atherosclerosis "as discussed by Liu (2007)". 5'-nucleotidase is important membrane-bound enzyme involved in the metabolism of extracellular nucleotides "as discussed elsewhere (Gorini, S., 2013; Buchheiser, A., 2011)". It catalyzes the hydrolysis of adenosine-monophosphate (AMP) generating adenosine that is a potent vasodilator and anti-inflammatory molecule and participates in numerous important biological functions and physiological effects, such as mediation of tubuloglomerular feedback, playing a crucial role in hypoxia-induced vascular leakage, acts as an endogenous modulator protecting against vascular inflammation and monocyte recruitment to limit the progression of atherosclerosis, and enable the efficient entry of lymphocytes into the central nervous system during autoimmune encephalitis "as discussed elsewhere (Burnstock, G., 2009)". It is becoming increasingly apparent that adenosine plays a central role in the regulation of the inflammatory response. 5'-nucleotidase is an enzyme normally expressed on vascular endothelial cells and a broad range of immune cells. Therefore, adenosine formed by extracellular nucleotide catabolism on endothelial cells and immune cells appears to be an important endogenous modulator of arteriogenesis, so it is obvious that the role of 5'-nucleotidase-derived adenosine in a model of chronic vascular inflammation such as atherogenesis. This establishes 5'-nucleotidase-derived adenosine as a direct or indirect regulator of atherogenesis "as discussed elsewhere (Boring, Y.C., 2013; Yamaguchi, H., 2014)".
The XOR is a ubiquitous enzyme essential in the last steps of purine metabolism, catalyzing the conversion of both hypoxanthine and xanthine to the end-product uric acid. XOR is widely distributed, occurring in milk, small intestine, predominantly in the liver and gastrointestinal tract but also in the kidney and brain. Interestingly, it is also found throughout the cardiovascular system and endothelial bound forms have been described. Expression of these has been shown to increase in ischaemia and in response to increased levels of proinflammatory cytokines "as discussed elsewhere (Szasz, T., 2013; Raghuvanshi, R., 2007; Higgins, P., 2009)". Besides uric acid, XOR also generates reactive oxygen species, specifically superoxide/hydrogen peroxide which serve as important signaling molecules in cardiovascular tissues. Increased ROS levels are a well-known pathogenetic factor in hypertension and cardiovascular disease "as discussed elsewhere (Van Hoorn, 2002)".
The XOR can specifically bind to endothelial cells and cell-bound XOR has been reported to produce radicals, which are inaccessible to CuZn-superoxide dismutase thus, during ischemia, ATP is degenerated to xanthine and hypoxanthine, thereby increasing XOR substrate levels, which leads to increased superoxide production. Excessive amounts of ROS in tissues also can cause implicated in ischemia and reperfusion injury that leads to atherosclerosis and chronic inflammation. The process of ageing is to a large extent due to the damaging consequence of free radical action (lipid peroxidation, DNA damage, protein oxidation) "as discussed elsewhere (Van Hoorn, 2002; Pala, F.S. and H. Gurkan, 2008). ROS, especially superoxide ([O2*.sup.-]) have been implicated in the pathogenesis of virtually every stage of vascular lesion formation in atherosclerosis. Atherosclerosis is a disease affecting arterial blood vessels. It is a chronic inflammatory response in the walls of arteries, in large part to the deposition of lipoproteins (plasma proteins that carry cholesterol and triglycerides). Oxidation of low density lipoprotein (LDL-cholesterol) was injurious to artery wall cells and suggested that LDL-cholesterol oxidation might be important in atherogenesis. The increase in XOR activity would then promote lipid peroxidation because XOR is expressed on the luminal surface of the endothelium (binds to the vascular endothelium) in many organs and catalysis the conversion of hypoxanthine into urate in a process that generates [O2*.sup.-] "as discussed elsewhere (Pongnimitprasert, N., 2009; Chang, Y.C., 2007)". Several possible mechanisms have been proposed in order to explain the association between increase levels of serum uric acid and CVD. First, there is evidence that increased uric acid levels promote oxidation of LDL-cholesterol and facilitate lipid peroxidation. In addition, increased uric acid levels are associated with increased production of oxygen free radicals which contribute to the initiation and progression of atherosclerosis. Moreover, the elevated uric acid levels are associated with increased platelet adhesiveness, and this effect could potentiate thrombus formation in patients with acute coronary syndromes. Uric acid has been shown to inhibit nitric oxide (NO) bioavailability. It has been reported that uric acid infusion in healthy humans resulted in impaired acetylcholine-induced vasodilation in the forearm, thereby documenting impaired endothelial NO release. Finally, Uric acid stimulates vascular smooth muscle cell proliferation "as discussed elsewhere (Papazafiropoulou, A., 2008; Pasalic, D., 2012)".
Serum proteins are useful indicators for initial screening of any abnormal function, inflammation and diseased condition. Circulating proteins are more stable in blood and serum with several individual markers as prospective biomarkers for the presence of atherosclerosis, myocardial infarction, heart failure, or markers of pathways involved in these cardiac conditions such as inflammation, thrombosis, plaque stability, and oxidative stress "as discussed by Laframboise (2012)".
In the present study, results indicate a decrease in serum protein, albumin and globulin/albumin (G/A) ratio. This is in agreement with the other studies "as discussed elsewhere (Hasan, A., 2004; Zecca, B., 2014)".
Increased venous pressure and abnormally dilated lymphatics can cause enteric loss of proteins. This has been seen in heart disease. Elevated venous pressure causes intestinal lymphangiectasia causing loss of albumin, protein, and lymphocytes in gut. Diagnosis is confirmed by finding low serum albumin and protein "as discussed by Hasan (2004)". It is widely reported that low albumin level and lower globulin/albumin (G/A) ratio correlates with an increased risk of cardiovascular diseases and atrial fibrillation "as discussed by Zecca (2014)".
The present study showed an increase level of the globulin in patients group when compared to control group. These results are similar to other study presented "as discussed by Zecca (2014)". The atherosclerosis has been considered as an inflammatory and immunizing disease. It is widely accepted that inflammation represents a risk factor for atrial fibrillation and for prothrombotic conditions. Different molecules behave differently during an inflammatory phase; albumin synthesis decreases, while other inflammatory globulins rise "as discussed by Zecca (2014)". The globulin fraction includes hundreds of serum proteins including carrier proteins, enzymes, complement, and immunoglobulins. Most of these are synthesized in the liver, although the immunoglobulins are synthesized by plasma cells, malnutrition and congenital immune deficiency can cause a decrease in total globulins due to decreased synthesis "as discussed by Mehdi (2014)".
The serum Crude of patients and control group was separated into distinct bands: albumin, [apha]1- and [alpha]2-globulins, [beta]1-and [beta]2-globulins and [gamma]-globulins and that the albumin had the maximum and gamma globulin had the minimum mobility in the electrical field, that is due to the fact that albumin is a protein with the most negative charges and it contains the most acidic amino acids with COO- groups "as discussed by Goljan (2008)" and it has a molecular weight of 69 kDa "as discussed by Chatterjea ", so it migrates furthest. In contrast, globulins are a large group of proteins, larger in size than albumin whose molecular weights range between 90-1300 kDa "as discussed by Chatterjea ",as well as it contains proteins with the most positive charges "as discussed by Goljan (2008)", so it remains close to the point of application.
According to this study, the increase in NSMCE2 may play a role in developments of change DNA damage in the patients with atherosclerosis, this observation has been detected for the first time to the best of our knowledge. In present study, a highly significant increase in 5'-nucleotidase levels in atherosclerosis patients explains that its adenosine can convey protection against atherosclerosis, an interference with intrinsic physiological pathways involved in the adenosine metabolism and 5'-nucleotidase is crucially involved in the finely tuned constitutive regulation balancing proinflammatory in the microvasculature. The increase in XOR activity detected in atherosclerosis patients reflects the detail that the catabolic pathway is increased in a way to produce hypoxanthine and xanthine in order to permit its readiness to recycle to IMP. As our knowledge, no previous studies have showed these results in atherosclerosis patients.
Received 4 September 2014
Received in revised form 24 November 2014
Accepted 8 December 2014
Available online 16 December 2014
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Nagham A. Jasim and Wesen A. Mehdi
Department of chemistry, College of sciences for women, university of Baghdad, Iraq
Corresponding Author: Nagham A. Jasim, Department of chemistry, College of sciences for women, university of Baghdad, Iraq.
Table 1: The mean and standard deviation of serum NSMCE2 [pg/ml] in patients and control groups. Studied group No. Mean [+ or -] SD Range Patients group 60 219.25 [+ or -] 52.04 98.52-337.98 Control group 30 101.82 [+ or -] 23.20 62.02-155.22 Total 90 Studied group Comparison of Significant p-Value Sig. Patients group 0.0001 Highly Significant Control group [p < 0.0001] Total Table 2: The mean and standard deviation of serum 5'-nucleotidase [U/L] in patients and control groups. Characteristic Patients group [n=60] Activities [U/L] Mean [+ or -] SD 49.05 [+ or -] 18.08 Range 25.19-119.84 Specific Activities [U/mg] Mean [+ or -] SD 0.72 [+ or -] 0.29 Range 0.35-2.02 Characteristic Control group [n=30] Activities [U/L] Mean [+ or -] SD 12.15 [+ or -] 3.97 Range 5.34-21.37 Specific Activities [U/mg] Mean [+ or -] SD 0.17 [+ or -] 0.05 Range 0.08-0.30 Characteristic Comparison of Significant p Value Sig. Activities [U/L] Mean [+ or -] SD 0.0007 Highly- Range Significant [p < 0.001] Specific Activities [U/mg] Mean [+ or -] SD 0.0004 Highly- Range Significant [p < 0.001] Table 3: The mean and standard deviation of serum XOR [U/L] in patients and control groups. Characteristic Patients group [n=60] Activities [U / L] Mean [+ or -] SD 54.56 [+ or -] 19.21 Range 15.06-155.00 Specific Activities [U/mg] Mean [+ or -] SD 0.79 [+ or -] 0.36 Range 0.20-2.23 Characteristic Control group [n=30] Activities [U / L] Mean [+ or -] SD 14.03 [+ or -] 3.46 Range 8.00-19.37 Specific Activities [U/mg] Mean [+ or -] SD 0.19 [+ or -] 0.05 Range 0.11-0.26 Characteristic Comparison of Significant p Value Sig. Activities [U / L] Mean [+ or -] SD 0.0006 Highly-Significant Range [p < 0.001] Specific Activities [U/mg] Mean [+ or -] SD 0.0008 Highly-Significant Range [p < 0.001] Table 4: The mean and standard deviation of serum uric acid [mmol/1] in patients and control groups. Studied group No. Mean [+ or -] SD Range Patients group 60 0.42 [+ or -] 0.06 0.29-0.52 Control group 30 0.31 [+ or -] 0.03 0.27-0.38 Total 90 Studied group Comparison of Significant p-Value Sig. Patients group 0.041 Significant Control group [p < 0.05] Total Table 5: Serum protein, albumin, globulin[gm/dl] and Alb./Glb. ratio in patients and control groups. Characteristic Patients Control group [n=60] group [n=30] S. protein [g/dl] Mean [+ or -] SD 6.91 [+ or -] 0.52 7.30 [+ or -] 0.51 Range 5.93-8.25 6.26-8.03 S. albumin [g/dl] Mean [+ or -] SD 3.93 [+ or -] 0.50 4.57 [+ or -] 0.57 Range 2.78-5.21 3.29-5.83 S. globulin[g/dl] Mean [+ or -] SD 2.99 [+ or -] 0.42 2.73 [+ or -] 0.47 Range 1.90-4.27 1.91-3.60 Alb./Glb. ratio Mean [+ or -] SD 1.38 [+ or -] 0.29 1.74 [+ or -] 0.47 Range 0.78-2.14 1.00-3.00 Characteristic Comparison of Significant p Value Sig. S. protein [g/dl] Mean [+ or -] SD 0.020 Significant Range [p < 0.05] S. albumin [g/dl] Mean [+ or -] SD 0.008 Significant Range [p < 0.01] S. globulin[g/dl] Mean [+ or -] SD 0.030 Significant Range [p < 0.05] Alb./Glb. ratio Mean [+ or -] SD 0.005 Significant Range [p < 0.01]
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|Author:||Jasim, Nagham A.; Mehdi, Wesen A.|
|Publication:||Advances in Natural and Applied Sciences|
|Article Type:||Clinical report|
|Date:||Feb 1, 2015|
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