Lipid Peroxidation, Protein Oxidation, Gelatinases, and Their Inhibitors in a Group of Adults with Obesity

Abstract

The association between obesity and cardiovascular diseases has a multifactorial pathogenesis, including the synthesis of inflammatory molecules, the increase in oxidative stress and the dysregulation of the matrix metalloprotease (MMP) concentration and activity. In a group of adults with obesity, divided in 2 subgroups according to the body mass index (BMI), we examined lipid peroxidation, expressed as thiobarbituric acid-reactive substances (TBARS), protein oxidation, expressed as protein carbonyl groups (PCs), plasma gelatinases (MMP-2 and MMP-9), and their tissue inhibitors (TIMP-1 and TIMP-2). In the whole group, as well as in the 2 subgroups (with BMI 30–35 or BMI>35) of obese subjects, we observed an increase in TBARS, PCs, MMP-2, and MMP-9, and also TIMP-1 and TIMP-2 in comparison with the control group. A positive correlation between TBARS and PCs emerged in obese subjects and persisted after dividing obese subjects according to BMI. The correlation between MMP-2 and TIMP-2 was not statistically significant, while a significant correlation was present between MMP-9 and TIMP-1. The correlations between the markers of oxidative stress (TBARS and PCs) and those of the MMP/TIMP profile indicated a more marked influence of protein oxidation on MMPs and TIMPs in comparison with TBARS. The innovative aspect of our study was the simultaneous evaluation of oxidative stress markers and MMP/TIMP profile in adult obese subjects. We observed significant alterations and correlations that may negatively influence the clinical course of the disease.

Key words

obesity - lipid peroxidation - protein oxidation - gelatinases - TIMPs

• References

• 1 Smith GD. A fatter, healthier but more unequal world. Lancet 2016; 387: 1349-1350
• 2 American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Obesity Expert Panel, 2013. Executive summary: Guidelines (2013) for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Obesity Society published by the Obesity Society and American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Based on a systematic review from the The Obesity Expert Panel, 2013. Obesity (Silver Spring) 2014; 22 (Suppl. 02) S5-S39
• 3 Yudkin JS, Kumari M, Humphries SE. et al. Inflammation, obesity, stress and coronary heart disease: Is interleukin-6 the link?. Atherosclerosis 2000; 148: 209-214
• 4 Díaz-Ruiz A, Guzmán-Ruiz R, Moreno NR. et al. Proteasome dysfunction associated to oxidative stress and proteotoxicity in adipocytes compromises insulin sensitivity in human obesity. Antioxid Redox Signal 2015; 23: 597-612
• 5 Huang CJ, McAllister MJ, Slusher AL. et al. Obesity-related oxidative stress: the impact of physical activity and diet manipulation. Sports Med Open 2015; 1: 32
• 6 Marseglia L, Manti S, D'Angelo G. et al. Oxidative stress in obesity: A critical component in human diseases. Int J Mol Sci 2015; 16: 378-400
• 7 Ruskovska T, Bernlohr DA. Oxidative stress and protein carbonylation in adipose tissue - implications for insulin resistance and diabetes mellitus. J Proteomics 2013; 92: 323-334
• 8 Ottobelli Chielle E, de Souza WM, da Silva TP. et al. Adipocytokines, inflammatory and oxidative stress markers of clinical relevance altered in young overweight/obese subjects. Clin Biochem 2016; 49: 548-553
• 9 Andrade VL, Petruceli E, Belo VA. et al. Evaluation of plasmatic MMP-8, MMP-9, TIMP-1 and MPO levels in obese and lean women. Clin Biochem 2012; 45: 412-415
• 10 Belo VA, Souza-Costa DC, Lana CM. et al. Assessment of matrix metalloproteinase (MMP)-2, MMP-8, MMP-9, and their inhibitors, the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in obese children and adolescents. Clin Biochem 2009; 42: 984-990
• 11 Dalle Donne I, Aldini G, Carini M. et al. Protein carbonylation, cellular dysfunction and disease progression. J Cell Mol Med 2006; 2: 389-406
• 12 Lubrano C, Valacchi G, Specchia P. et al. Integrated haematological profiles of redox status, lipid, and inflammatory protein biomarkers in benign obesity and unhealthy obesity with metabolic syndrome. Oxid Med Cell Longev 2015; 2015; 490613
• 13 Venturini D, Simao AN, Dichi I. Advanced oxidation protein products are more related to metabolic syndrome components than biomarkers of lipid peroxidation. Nutr Res 2015; 35: 759-765
• 14 Sledzinski T, Goyke E, Smolenski RT. et al. Decrease in serum protein carbonyl groups concentration and maintained hyperhomocysteinemia in patients undergoing bariatric surgery. Obes Surg 2009; 19: 321-326
• 15 Cervellati C, Bonaccorsi G, Cremonini E. et al. Waist circumference and dual-energy X-ray absorptiometry measures of overall and central obesity are similarly associated with systemic oxidative stress in women. Scand J Clin Lab Invest 2014; 74: 102-107
• 16 Furukawa S, Fujita K, Shimabukuro M. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761
• 17 Palmieri VO, Grattagliano I, Portincasa P. et al. Systemic oxidative alterations are associated with visceral adiposity and liver steatosis in patients with metabolic syndrome. J Nutr 2006; 136: 3022-3026
• 18 Fujita K, Nishizawa H, Funahashi T. et al. Systemic oxidative stress is associated with visceral fat accumulation and the metabolic syndrome. Circ J 2006; 70: 1437-1442
• 19 Pandey G, Shihabudeen MS, David HP. et al. Association between hyperleptinemia and oxidative stress in obese diabetic subjects. J Diabetes Metab Disord 2015; 14: 24
• 20 Albuali WH. Evaluation of oxidant-antioxidant status in overweight and morbidly obese Saudi children. World J Clin Pediatr 2014; 3: 6-13
• 21 Krzystek-Korpacka M, Patryn E, Boehm D. et al. Advanced oxidation protein products (AOPPs) in juvenile overweight and obesity prior to and following weight reduction. Clin Biochem 2008; 41: 943-949
• 22 Medeiros Nda S, de Abreu FG, Colato AS et al. Effects of concurrent training on oxidative stress and insulin resistance in obese individuals. Oxid Med Cell Longev 2015; 697181:
• 23 Chavey C, Mari B, Monthouel MN. et al. Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem 2003; 278: 11888-11896
• 24 Catalán V, Gómez-Ambrosi J, Rodríguez A. et al. Increased adipose tissue expression of lipocalin-2 in obesity is related to inflammation and matrix metalloproteinase-2 and metalloproteinase-9 activities in humans. J Mol Med (Berl) 2009; 87: 803-813
• 25 Hayden MR, Sowers JR, Tyagi SC. The central role of vascular extracellular matrix and basement membrane remodeling in metabolic syndrome and type 2 diabetes: The matrix preloaded. Cardiovasc Diabetol 2005; 4: 9
• 26 Newby AC. Metalloproteinases expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol 2008; 28: 2108-2114
• 27 Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 2008; 75: 346-359
• 28 Amalinei C, Caruntu ID, Balan RA. Biology of metalloproteinases. Rom J Morphol Embryol 2007; 48: 323-334
• 29 Liu P, Sun M, Sader S. Matrix metalloproteinases in cardiovascular disease. Can J Cardiol 2006; 22: 25B-30B
• 30 Hansson J, Vasan RS, Anlov J. et al. Biomarkers of extracellular matrix metabolism (MMP-9 and TIMP-1) and risk of stroke, myocardial infarction, and cause-specific mortality: Cohort Study. PLoS One 2011; 6: e16185
• 31 Kameda K, Matsunaga T, Abe N. et al. Correlation of oxidative stress with activity of matrix metalloproteinase in patients with coronary artery disease. Possible role for left ventricular remodelling. Eur Heart J 2003; 24: 2180-2185
• 32 Nagareddy P, Rajput P, Vasudevan H. et al. Inhibition of matrix metalloproteinase-2 improves endothelial function and prevents hypertension in insulin resistant rats. Br J Pharmacol 2012; 165: 705-715
• 33 Kosmala W, Plaksej R, Przewlocka-Kosmala M. et al. Matrix metalloproteinases 2 and 9 and their tissue inhibitors 1 and 2 in premenopausal obese women: relationship to cardiac function. Int J Obes (Lond) 2008; 32: 763-771
• 34 Derosa G, Ferrari I, D'Angelo A. et al. Matrix metalloproteinase-2 and -9 levels in obese patients. Endothelium 2008; 15: 219-224
• 35 Luizon MR, Belo VA, Fernandes KS. et al. Plasma matrix metalloproteinase-9 levels, MMP-9 gene haplotypes, and cardiovascular risk in obese subjects. Mol Biol Rep 2016; 43: 463-471
• 36 Miksztowicz V, Muzzio ML, Royer M. et al. Increased plasma activity of metalloproteinase 2 in women with metabolic syndrome. Metabolism 2008; 57: 1493-1496
• 37 Miksztowicz V, Fernandez Machulsky N. et al. Adiponectin predicts MMP-2 activity independently of obesity. Eur J Clin Invest 2014; 44: 951-957
• 38 Głowinska-Olszewska B, Urban M. Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents. Metabolism 2007; 56: 799-805
• 39 Belo VA, Lacchini R, Miranda JA. et al. Increased activity of MMP-2 in hypertensive obese children is associated with hypoadiponectinemia. Obesity (Silver Spring) 2015; 23: 177-182
• 40 Laimer M, Kaser S, Kranebitter M. et al. Effect of pronounced weight loss on the nontraditional cardiovascular risk marker matrix metalloproteinase-9 in middle-aged morbidly obese women. Int J Obes (Lond) 2005; 29: 498-501
• 41 Madsen EL, Bruun JM, Skogstrand K. et al. Long-term weight loss decreases the nontraditional cardiovascular risk factors interleukin-18 and matrix metalloproteinase–9 in obese subjects. Metab Clin Exp 2009; 58: 946-953
• 42 Papazoglou D, Papatheodorou K, Papanas N. et al. Matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 levels in severely obese patients: what is the effect of weight loss?. Exp Clin Endocrinol Diabetes 2010; 118: 730-734
• 43 Lee YJ, Heo YS, Park HS. et al. Serum SPARC and matrix metalloproteinase-2 and metalloproteinase-9 concentrations after bariatric surgery in obese adults. Obes Surg 2014; 24: 604-610
• 44 Lowry OH, Rosebrough NJ, Farr AL. et al. Protein measurement with the Folin-phenol reagent. J Biol Chem 1951; 193: 265-275
• 45 D'Archivio M, Annuzzi G, Varì R. et al. Predominant role of obesity/insulin resistance in oxidative stress development. Eur J Clin Invest 2012; 42: 70-78
• 46 Codoner-Franch P, Boix-García L, Simó-Jordá R. et al. Is obesity associated with oxidative stress in children?. Int J Pediatr Obes 2010; 5: 56-63
• 47 Belo VA, Luizon MR, Carneiro PC. et al. Effect of metabolic syndrome risk factors and MMP-2 genetic variations on circulating MMP-2 levels in childhood obesity. Mol Biol Rep 2013; 40: 2697-2704
• 48 Shin YH, Kim KE, Lee YJ. et al. Associations of matrix metalloproteinase (MMP)-8, MMP-9, and their inhibitor, tissue inhibitor of metalloproteinase-1, with obesity-related biomarkers in apparently healthy adolescent boys. Korean J Pediatr 2014; 57: 526-532
• 49 Uzun H, Konukoglu D, Gelisgen R. et al. Plasma protein carbonyl and thiol stress before and after laparoscopic gastric banding in morbidly obese patients. Obes Surg 2007; 17: 1367-1373
• 50 Amirkhizi F, Siassi F, Minaie S. et al. Is obesity associated with increased plasma lipid peroxidation and oxidatve stress in women?. ARYA Atheroscler J 2007; 2: 189-192
• 51 Stefanovic A, Kotur-Stevuljevic J, Spasic S. et al. The influence of obesity on the oxidative stress status and the concentration of leptin in type 2 diabetes mellitus patients. Diabetes Res Clin Pract 2008; 79: 156-163
• 52 Tinahones FJ, Murri-Pierri M, Garrido-Sánchez L. et al. Oxidative stress in severely obese persons is greater in those with insulin resistance. Obesity (Silver Spring) 2009; 17: 240-246
• 53 Frohnert BI, Sinaiko AR, Serrot FJ. et al. Increased adipose protein carbonylation in human obesity. Obesity (Silver Spring) 2011; 19: 1735-1741
• 54 Venturini D, Simao AN, Scripes NA. et al. Evaluation of oxidative stress in overweight subjects with or without metabolic syndrome. Obesity (Silver Spring) 2012; 20: 2361-2366
• 55 Catoi AF, Parvu A, Galea RF. et al. Nitric oxide, oxidant status and antioxidant response in morbidly obese patients: The impact of 1-year surgical weight loss. Obes Surg 2013; 23: 1858-1863
• 56 Gaxiola-Robles R, Bitzer-Quintero OK, Méndez-Rodríguez LC. et al. Lipid peroxidation and the response of the antioxidant defense system in the obese type 2 diabetic compared with the non-obese type 2 diabetic. Nutr Hosp 2013; 28: 1905-1911
• 57 Bollineni RC, Fedorova M, Blüher M. et al. Carbonylated plasma proteins as potential biomarkers of obesity induced type 2 diabetes mellitus. J Proteome Res 2014; 13: 5081-5093
• 58 Gariballa S, Kosanovic M, Yasin J. et al. Oxidative damage and inflammation in obese diabetic Emirati subjects. Nutrients 2014; 6: 4872-4880
• 59 Jones DA, Prior SL, Barry JD. et al. Changes in markers of oxidative stress and DNA damage in human visceral adipose tissue from subjects with obesity and type 2 diabetes. Diabetes Res Clin Pract 2014; 106: 627-633
• 60 Hopps E, Canino B, Calandrino V. et al. Lipid peroxidation and protein oxidation are related to the severity of OSAS. Eur Rev Med Pharmacol Sci 2014; 18: 3773-3778
• 61 Hopps E, Lo Presti R, Montana M et al. Study of the correlations among some parameters of the oxidative status, gelatinases, and their inhibitors in a group of subjects with metabolic syndrome. Mediators Inflamm 2014; 510619:
• 62 Hopps E, Lo Presti R, Montana M. et al. Analysis of the correlations between oxidative stress, gelatinases and their tissue inhibitors in the human subjects with obstructive sleep apnea syndrome. J Physiol Pharmacol 2015; 66: 803-810
• 63 Vincent HK, Bourguignon C, Vincent KR. Resistance training lowers exercise-induced oxidative stress and homocysteine levels in overweight and obese older adults. Obesity (Silver Spring) 2006; 14: 1921-1930
• 64 Domienik-Karlowicz J, Rymarczyk Z, Dzikowska-Diduch O. et al. Emerging markers of atherosclerosis before and after bariatric surgery. Obes Surg 2015; 25: 486-493
• 65 Bittner A, Alcaíno H, Castro PF. et al. Matrix metalloproteinase-9 activity is associated to oxidative stress in patients with acute coronary syndrome. Int J Cardiol 2010; 143: 98-100
• 66 Kelly PJ, Morrow JD, Ning M. et al. Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: The Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study. Stroke 2008; 39: 100-104
• 67 Pawlak K, Tankiewicz J, Mysliwiec M. et al. Systemic levels of MMP2/TIMP2 and cardiovascular risk in CAPD patients. Nephron Clin Pract 2010; 115: c251-c258
• 68 Kandasamy AD, Chow AK, Ali MA. et al. Matrix metalloproteinase-2 and myocardial oxidative stress injury: Beyond the matrix. Cardiovasc Res 2010; 85: 413-423
• 69 Brown DJ, Lin B, Chwa M. et al. Elements of the nitric oxide pathway can degrade TIMP-1 and increase gelatinase activity. Mol Vis 2004; 10: 281-288
• 70 Donnini S, Monti M, Roncone R. et al. Peroxynitrite inactivates human-tissue inhibitor of metalloproteinase-4. FEBS Lett 2008; 582: 1135-1140
• 71 Viappiani S, Nicolescu AC, Holt A. et al. Activation and modulation of 72kDa matrix metalloproteinase-2 by peroxynitrite and glutathione. Biochem Pharmacol 2009; 77: 826-834
• 72 Koken T, Gursoy F, Kahraman A. Long-term alcohol consumption increases Pro-Matrix Metalloproteinase-9 levels via oxidative stress. J Med Toxicol 2010; 6: 126-130
• 73 Kar S, Subbaram S, Carrico PM. et al. A critical link between free radicals, matrix remodeling and degenerative disease. Respir Physiol Neurobiol 2010; 174: 299-306
• 74 Soumyarani VS, Jayakumari N. Oxidatively modified high density lipoprotein promotes inflammatory response in human monocytes-macrophages by enhanced production of ROS, TNF-α, MMP-9, and MMP-2. Mol Cell Biochem 2012; 366: 277-285
• 75 Uemura S, Matsushita H, Li W. et al. Diabetes mellitus enhances vascular matrix metalloproteinase activity: Role of oxidative stress. Circ Res 2001; 88: 1291-1298
• 76 Ho FM, Liu SH, Lin WW. et al. Opposite effects of high glucose on MMP-2 and TIMP-2 in human endothelial cells. Cell Biochem 2007; 101: 442-450
• 77 Death AK, Fisher EJ, McGrafth KC. et al. High glucose alters matrix metalloproteinase expression in two key vascular cells: Potential impact on atherosclerosis in diabetes. Atherosclerosis 2003; 168: 263-269
• 78 Spinale FG. Matrix metalloproteinases: Regulation and dysregulation in the failing heart. Circ Res 2002; 90: 520-530
• 79 Altieri P, Brunelli C, Garibaldi S. et al. Metalloproteinases 2 and 9 are increased in plasma of patients with heart failure. Eur J Clin Invest 2003; 33: 648-656
• 80 Spinale FG, Zile MR. Integrating the myocardial matrix into heart failure recognition and management. Circ Res 2013; 113: 725-738
• 81 Spinale FG, Janicki JS, Zile MR. Membrane-associated matrix proteolysis and heart failure. Circ Res 2013; 112: 195-208
• 82 Webb CS, Bonnema DD, Ahmed SH. et al. Specific temporal profile of matrix metalloproteinase release occurs in patients after myocardial infarction: Relation to left ventricular remodeling. Circulation 2006; 114: 1020-1027
• 83 Lindsey ML, Zamilpa R. Temporal and spatial expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases following myocardial infarction. Cardiovasc Ther 2012; 30: 31-41
• 84 Lindsey ML, Iyer RP, Jung M. et al. Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling. J Mol Cell Cardiol 2016; 91: 134-140
• 85 Ahmed SH, Clark LL, Pennington WR. et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 2006; 113: 2089-2096
• 86 Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: Influence on cardiac form and function. Physiol Rev 2007; 87: 1285-1342
• 87 Sebekova K, Boor P, Valachovicova M. et al. Association of metabolic syndrome risk factors with selected markers of oxidative status and microinflammation in healthy omnivores and vegetarians. Mol Nutr Food Res 2006; 50: 858-868