The AGE-RAGE Axis and Its Relationship to Markers of Cardiovascular Disease in Newly Diagnosed Diabetic Patients

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Jul 20

PMID 27434539

Citations 16

Authors

Ma Etzabel Villegas-Rodriguez

Jaime Uribarri

Sergio E Solorio-Meza

Martha E Fajardo-Araujo

Weijing Cai

Sofia Torres-Graciano

Ruben Rangel-Salazar

Kazimierz Wrobel

Ma Eugenia Garay-Sevilla

Affiliations

Soon will be listed here.

Abstract

Aim: The purpose of the study was the simultaneous measurement of all the different components of the AGE-RAGE axis as well as several non-invasive markers of cardiovascular disease (CVD) in a cohort of newly diagnosed diabetic patients.

Materials And Methods: In 80 newly diagnosed diabetic patients we measured serum carboxymethyllysine (CML), soluble RAGE (sRAGE) and peripheral mononuclear (PMNC) RAGE and AGER1 mRNA together with ICAM-1, VCAM-1, and malondialdehyde (MDA). We also assessed cardiovascular function by measurement of flow-mediated vasodilation (FMD), intima-media thickness (IMT) and arterial stiffness. Univariant correlation analysis was used to determine correlation between the variables in the study and multiple regression analysis was used to examine the association between the AGE-RAGE axis components and FMD, IMT and arterial stiffness.

Results: Serum CML correlated positively with sRAGE, PMNC RAGE, HOMA-IR, ICAM-1, VCAM-1 and MDA, but inversely with PMNC AGER1. sRAGE and RAGE was positively correlated with AGER; IMT was positively correlated with HOMA-IR, ICAM-1, VCAM-1, MDA, and sRAGE and arterial stiffness had correlation with HOMA-IR, ICAM-1, VCAM-1, MDA, CML, sRAGE, AGER1 and RAGE. In multivariate analysis we found a significant relationship between CML with PMNC RAGE, HOMA-IR; sRAGE with VCAM-1 and MDA; PMNC RAGE with PMNC AGER1and CML; PMNC AGER1 with PMNC RAGE; FMD with sRAGE, CML and HbA1c; IMT with sRAGE, and arterial stiffness with sRAGE, sCML and AGER1.

Conclusions: We found significant and strong associations between the different components of the AGE-RAGE axis and also found significant association between AGE-RAGE axis markers, especially sRAGE with several noninvasive markers of cardiovascular disease risk. sRAGE, an easily measured parameter in blood, may potentially be used as a surrogate marker of AGEs-RAGE in patients with diabetes.

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References

Wilk G, Osmenda G, Matusik P, Nowakowski D, Jasiewicz-Honkisz B, Ignacak A . Endothelial function assessment in atherosclerosis: comparison of brachial artery flow‑mediated vasodilation and peripheral arterial tonometry. Pol Arch Med Wewn. 2013; 123(9):443-52. DOI: 10.20452/pamw.1879. View

Montalcini T, Romeo S, Fava A, Pujia A . Carotid intima-media thickness: a target or a marker?. Am J Ther. 2012; 21(6):535-9. DOI: 10.1097/MJT.0b013e318255bc26. View

Ruszkowska-Ciastek B, Sokup A, Wernik T, Ruprecht Z, Goralczyk B, Goralczyk K . Effect of uncontrolled hyperglycemia on levels of adhesion molecules in patients with diabetes mellitus type 2. J Zhejiang Univ Sci B. 2015; 16(5):355-61. PMC: 4432987. DOI: 10.1631/jzus.B1400218. View

Nakamura K, Yamagishi S, Matsui T, Adachi H, Takeuchi M, Imaizumi T . Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are correlated with AGEs in both diabetic and non-diabetic subjects. Clin Exp Med. 2008; 7(4):188-90. DOI: 10.1007/s10238-007-0146-7. View

Flore R, Ponziani F, Tinelli G, Arena V, Fonnesu C, Nesci A . New modalities of ultrasound-based intima-media thickness, arterial stiffness and non-coronary vascular calcifications detection to assess cardiovascular risk. Eur Rev Med Pharmacol Sci. 2015; 19(8):1430-41. View

Lee H, Oh B . Aging and arterial stiffness. Circ J. 2010; 74(11):2257-62. DOI: 10.1253/circj.cj-10-0910. View

Timmis A . Diabetic heart disease: clinical considerations. Heart. 2001; 85(4):463-9. PMC: 1729682. DOI: 10.1136/heart.85.4.463. View

Arrebola-Moreno A, Laclaustra M, Kaski J . Noninvasive assessment of endothelial function in clinical practice. Rev Esp Cardiol (Engl Ed). 2011; 65(1):80-90. DOI: 10.1016/j.recesp.2011.09.012. View

Biswas S, Mohtarin S, Mudi S, Anwar T, Banu L, Alam S . Relationship of Soluble RAGE with Insulin Resistance and Beta Cell Function during Development of Type 2 Diabetes Mellitus. J Diabetes Res. 2015; 2015:150325. PMC: 4452360. DOI: 10.1155/2015/150325. View

10.

Uribarri J, Cai W, Sandu O, Peppa M, Goldberg T, Vlassara H . Diet-derived advanced glycation end products are major contributors to the body's AGE pool and induce inflammation in healthy subjects. Ann N Y Acad Sci. 2005; 1043:461-6. DOI: 10.1196/annals.1333.052. View

11.

Charakida M, Masi S, Luscher T, Kastelein J, Deanfield J . Assessment of atherosclerosis: the role of flow-mediated dilatation. Eur Heart J. 2010; 31(23):2854-61. DOI: 10.1093/eurheartj/ehq340. View

12.

Goldin A, Beckman J, Schmidt A, Creager M . Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006; 114(6):597-605. DOI: 10.1161/CIRCULATIONAHA.106.621854. View

13.

Tahara N, Yamagishi S, Matsui T, Takeuchi M, Nitta Y, Kodama N . Serum levels of advanced glycation end products (AGEs) are independent correlates of insulin resistance in nondiabetic subjects. Cardiovasc Ther. 2010; 30(1):42-8. DOI: 10.1111/j.1755-5922.2010.00177.x. View

14.

Chiang K, Huang P, Huang S, Wu T, Chen J, Lin S . Plasma levels of soluble receptor for advanced glycation end products are associated with endothelial function and predict cardiovascular events in nondiabetic patients. Coron Artery Dis. 2009; 20(4):267-73. DOI: 10.1097/MCA.0b013e32832c459c. View

15.

Mitchell G, Hwang S, Vasan R, Larson M, Pencina M, Hamburg N . Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010; 121(4):505-11. PMC: 2836717. DOI: 10.1161/CIRCULATIONAHA.109.886655. View

16.

Smriti K, Pai K, Ravindranath V, Pentapati K . Role of salivary malondialdehyde in assessment of oxidative stress among diabetics. J Oral Biol Craniofac Res. 2016; 6(1):41-4. PMC: 4756067. DOI: 10.1016/j.jobcr.2015.12.004. View

17.

Di Pino A, Scicali R, Calanna S, Urbano F, Mantegna C, Rabuazzo A . Cardiovascular risk profile in subjects with prediabetes and new-onset type 2 diabetes identified by HbA(1c) according to American Diabetes Association criteria. Diabetes Care. 2014; 37(5):1447-53. DOI: 10.2337/dc13-2357. View

18.

Vlassara H, Striker G . AGE restriction in diabetes mellitus: a paradigm shift. Nat Rev Endocrinol. 2011; 7(9):526-39. PMC: 3708644. DOI: 10.1038/nrendo.2011.74. View

19.

Mackenzie I, Wilkinson I, Cockcroft J . Assessment of arterial stiffness in clinical practice. QJM. 2002; 95(2):67-74. DOI: 10.1093/qjmed/95.2.67. View

20.

Lu C, He J, Cai W, Liu H, Zhu L, Vlassara H . Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells. Proc Natl Acad Sci U S A. 2004; 101(32):11767-72. PMC: 511050. DOI: 10.1073/pnas.0401588101. View