Inverse Association between Cardiac Troponin-I and Soluble Receptor for Advanced Glycation End Products in Patients with Non-ST-Segment Elevation Myocardial Infarction

ABSTRACT

Interaction of advanced glycation end products (AGEs) with the receptor for advanced AGEs (RAGE) results in activation of nuclear factor kappa-B, release of cytokines, expression of adhesion molecules, and induction of oxidative stress. Oxygen radicals are involved in plaque rupture contributing to thromboembolism, resulting in acute coronary syndrome (ACS). Thromboembolism and the direct effect of oxygen radicals on myocardial cells cause cardiac damage that results in the release of cardiac troponin-I (cTnI) and other biochemical markers. The soluble RAGE (sRAGE) compete with RAGE for binding with AGE, thus functioning as a decoy and exerting a cytoprotective effect. Low levels of serum sRAGE would allow unopposed serum AGE availability for binding with RAGE, resulting in the generation of oxygen radicals and proinflammatory molecules that have deleterious consequences and promote myocardial damage. sRAGE may stabilize atherosclerotic plaques. It is hypothesized that low levels of sRAGE are associated with high levels of serum cTnI in patients with ACS. The main objective of the study was to determine whether low levels of serum sRAGE are associated with high levels of serum cTnI in ACS patients. The serum levels of sRAGE and cTnI were measured in 36 patients with non-ST-segment elevation myocardial infarction (NSTEMI) and 30 control subjects. Serum levels of sRAGE were lower in NSTEMI patients (802.56 ± 39.32 pg/mL) as compared with control subjects (1311.43 ± 66.92 pg/mL). The levels of cTnI were higher in NSTEMI patients (2.18 ± 0.33 μg/mL) as compared with control subjects (0.012 ± 0.001 μg/mL). Serum sRAGE levels were negatively correlated with the levels of cTnI. In conclusion, the data suggest that low levels of serum sRAGE are associated with high serum levels of cTnI and that there is a negative correlation between sRAGE and cTnI.

Soluble receptor for advanced glycation end products - cardiac troponin-I - non-ST-elevation mycardial infarction - cytokines - oxidative stress - thromboembolism

REFERENCES

• 1 Eisenman A. Troponin assays for the diagnosis of myocardial infarction and acute coronary syndrome: where do we stand?.  Expert Rev Cardiovasc Ther. 2006;  4 509-514
• 2 Babuin L, Jaffe A S. Troponin: the biomarker of choice for the detection of cardiac injury.  CMAJ. 2005;  173 1191-1202
• 3 Braunwald E, Antman E M, Beasley J W American College of Cardiology et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).  J Am Coll Cardiol. 2002;  40 1366-1374
• 4 Braunwald E, Antman E M, Beasley J W et al.. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina).  J Am Coll Cardiol. 2000;  36 970-1062
• 5 Alpert J S, Thygesen K, Antman E, Bassand J P. Joint European Society of Cardiology/ American College of Cardiology Committee . Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.  J Am Coll Cardiol. 2000;  36 959-969
• 6 Jaffe A S, Ravkilde J, Roberts R et al.. It's time for a change to a troponin standard.  (editorial) Circulation. 2000;  102 1216-1220
• 7 Bertrand M E, Simoons M L, Fox K A et al.. Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation; recommendations of the Task Force of the European Society of Cardiology.  Eur Heart J. 2000;  21 1406-1432
• 8 Apple F S, Murakami M M. Cardiac troponin and creatine kinase MB monitoring during in-hospital myocardial reinfarction.  Clin Chem. 2005;  51 460-463
• 9 Apple F S, Murakami M M, Quist H H, Pearce L A, Wieczorek S, Wu A HB. Prognostic value of the Ortho Vitros cardiac troponin I assay in patients with symptoms of myocardial ischemia. Risk stratification using European Society of Cardiology/American College of Cardiology recommended cutoff values.  Am J Clin Pathol. 2003;  120 114-120
• 10 Bucala R, Cerami A. Advanced glycosylation: chemistry, biology, and implications for diabetes and aging.  Adv Pharmacol. 1992;  23 1-34
• 11 Prasad K. Soluble receptors for advanced glycation end products (sRAGE) and cardiovascular disease.  Int J Angiol. 2006;  15 57-68
• 12 Schmidt A M, Yan S D, Yan S F, Stern D M. The biology of the receptor for advanced glycation end products and its ligands.  Biochim Biophys Acta. 2000;  1498 99-111
• 13 Yonekura H, Yamamoto Y, Sakurai S et al.. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury.  Biochem J. 2003;  370 (Pt 3) 1097-1109
• 14 Hudson B I, Harja E, Moser B, Schmidt A M. Soluble levels of receptor for advanced glycation endproducts (sRAGE) and coronary artery disease: the next C-reactive protein?.  Arterioscler Thromb Vasc Biol. 2005;  25 879-882
• 15 Hofmann M A, Drury S, Fu C et al.. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.  Cell. 1999;  97 889-901
• 16 Reznikov L L, Waksman J, Azam T et al.. Effect of advanced glycation end products on endotoxin-induced TNF-alpha, IL-1beta and IL-8 in human peripheral blood mononuclear cells.  Clin Nephrol. 2004;  61 324-336
• 17 Yan S D, Schmidt A M, Anderson G M et al.. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins.  J Biol Chem. 1994;  269 9889-9897
• 18 Wautier M P, Chappey O, Corda S, Stern D M, Schmidt A M, Wautier J L. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE.  Am J Physiol Endocrinol Metab. 2001;  280 E685-E694
• 19 Braquet P, Hosford D, Braquet M, Bourgain R, Bussolino F. Role of cytokines and platelet-activating factor in microvascular immune injury.  Int Arch Allergy Appl Immunol. 1989;  88 88-100
• 20 Wang Q, Doerschuk C M, Mizgerd J P. Neutrophils in innate immunity.  Semin Respir Crit Care Med. 2004;  25 33-41
• 21 Yuo A, Kitagawa S, Kasahara T, Matsushima K, Saito M, Takaku F. Stimulation and priming of human neutrophils by interleukin-8: cooperation with tumor necrosis factor and colony-stimulating factors.  Blood. 1991;  78 2708-2714
• 22 Gertzberg N, Neumann P, Rizzo V, Johnson A. NAD(P)H oxidase mediates the endothelial barrier dysfunction induced by TNF-alpha.  Am J Physiol Lung Cell Mol Physiol. 2004;  286 L37-L48
• 23 Nwariaku F E, Liu Z, Zhu X et al.. NADPH oxidase mediates vascular endothelial cadherin phosphorylation and endothelial dysfunction.  Blood. 2004;  104 3214-3220
• 24 Freeman B A, Crapo J D. Biology of disease: free radicals and tissue injury.  Lab Invest. 1982;  47 412-426
• 25 Meerson F Z, Kagan V E, Kozlov YuP, Belkina L M, Arkhipenko YuV. The role of lipid peroxidation in pathogenesis of ischemic damage and the antioxidant protection of the heart.  Basic Res Cardiol. 1982;  77 465-485
• 26 Prasad K, Lee P, Mantha S V, Kalra J, Prasad M, Gupta J B. Detection of ischemia-reperfusion cardiac injury by cardiac muscle chemiluminescence.  Mol Cell Biochem. 1992;  115 49-58
• 27 Jolly S R, Kane W J, Bailie M B, Abrams G D, Lucchesi B R. Canine myocardial reperfusion injury. Its reduction by the combined administration of superoxide dismutase and catalase.  Circ Res. 1984;  54 277-285
• 28 Prasad K, Kalra J, Chan W P, Chaudhary A K. Effect of oxygen free radicals on cardiovascular function at organ and cellular levels.  Am Heart J. 1989;  117 1196-1202
• 29 Prasad K, Kalra J, Chaudhary A K, Debnath D. Effect of polymorphonuclear leukocyte-derived oxygen free radicals and hypochlorous acid on cardiac function and some biochemical parameters.  Am Heart J. 1990;  119 538-550
• 30 Prasad K, Debnath D, Kalra J, Lee P. Effects of dimethylthiourea on the cardiac function and oxyradical status in ischemia-reperfusion injury.  Ann N Y Acad Sci. 1994;  723 375-379
• 31 Hiebert L M, Liu J M. Heparin protects cultured arterial endothelial cells from damage by toxic oxygen metabolites.  Atherosclerosis. 1990;  83 47-51
• 32 Kalra J, Chaudhary A K, Massey K L, Prasad K. Effect of oxygen free radicals, hypoxia and pH on the release of liver lysosomal enzymes.  Mol Cell Biochem. 1990;  94 1-8
• 33 Geroldi D, Falcone C, Emanuele E. Soluble receptor for advanced glycation end products: from disease marker to potential therapeutic target.  Curr Med Chem. 2006;  13 1971-1978
• 34 Galis Z S, Sukhova G K, Lark M W, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.  J Clin Invest. 1994;  94 2493-2503
• 35 Nikkari S T, O'Brien K D, Ferguson M et al.. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis.  Circulation. 1995;  92 1393-1398
• 36 Shah P K, Falk E, Badimon J J et al.. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture.  Circulation. 1995;  92 1565-1569
• 37 Constantinides P. Plaque hemorrhages, their genesis and their role in supra-plaque thrombosis and atherogenesis. In: Glasgov S, Newman W PI, Schafer S A, eds. Pathology of the Human Atherosclerotic Plaque. New York: Springer-Verlag; 1999: 393-412
• 38 Falk E, Shah P K, Fuster V. Coronary plaque disruption.  Circulation. 1995;  92 657-671
• 39 Rajagopalan S, Meng X P, Ramasamy S, Harrison D G, Galis Z S. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability.  J Clin Invest. 1996;  98 2572-2579
• 40 Cipollone F, Iezzi A, Fazia M et al.. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control.  Circulation. 2003;  108 1070-1077
• 41 Cuccurullo C, Iezzi A, Fazia M L et al.. Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes.  Arterioscler Thromb Vasc Biol. 2006;  26 2716-2723
• 42 McNair E D, Wells C R, Qureshi A M et al.. Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients.  Int J Angiol. 2009;  18 187-192
• 43 Boyle J J. Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture.  Curr Vasc Pharmacol. 2005;  3 63-68
• 44 Arroyo L H, Lee R T. Mechanisms of plaque rupture: mechanical and biologic interactions.  Cardiovasc Res. 1999;  41 369-375
• 45 Kasap S, Gönenç A, Sener D E, Hisar I. Serum cardiac markers in patients with acute myocardial infarction: oxidative stress, C-reactive protein and N-terminal probrain natriuretic peptide.  J Clin Biochem Nutr. 2007;  41 50-57
• 46 Iqbal K, Rauoof M A, Mir M M et al.. Lipid peroxidation during acute coronary syndromes and its intensification at the time of myocardial ischemia reperfusion.  Am J Cardiol. 2002;  89 334-337
• 47 McNair E, Wells C, Qureshi A, Prasad K. Homocysteine and malondialdehyde as predictors of restenosis following percutaneous coronary intervention.  Int J Angiol. 2006;  15 69-75