CC BY 4.0 · Aorta (Stamford) 2016; 04(01): 1-10
DOI: 10.12945/j.aorta.2015.15.018
Original Research Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Advanced Glycation End Products and its Soluble Receptors in the Pathogenesis of Thoracic Aortic Aneurysm

Kailash Prasad
1   Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
,
Abdullah Sarkar
2   Aortic Institute at Yale-New Haven, Yale University School of Medicine, Connecticut, USA
3   College of Medicine, Alfaisal University, Ryadh, Saudi Arabia
,
Mohammad A. Zafar
2   Aortic Institute at Yale-New Haven, Yale University School of Medicine, Connecticut, USA
,
Ahmed Shoker
4   Department of Medicine, Royal University Hospital, Saskatoon, Saskatchewan, Canada
,
Hamdi EI Moselhi
4   Department of Medicine, Royal University Hospital, Saskatoon, Saskatchewan, Canada
,
Maryann Tranquilli
2   Aortic Institute at Yale-New Haven, Yale University School of Medicine, Connecticut, USA
,
Bulat A. Ziganshin
2   Aortic Institute at Yale-New Haven, Yale University School of Medicine, Connecticut, USA
5   Department of Surgical Diseases #2, Kazan State Medical University, Kazan, Russia
,
John A. Elefteriades
2   Aortic Institute at Yale-New Haven, Yale University School of Medicine, Connecticut, USA
› Author Affiliations
Further Information

Publication History

11 February 2015

06 May 2015

Publication Date:
24 September 2018 (online)

Abstract

Background: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of thoracic aortic aneurysms (TAAs). Cytokines [Interleukin (IL)-Iβ, IL-2, IL-6, and TNF-α)] increase the expression of MMP-2 and -3. Advanced glycation end products (AGEs) interact with cell receptors to increase the release of cytokines. Circulating soluble receptors for AGEs (sRAGE) and endogenous secretory RAGE (esRAGE) compete with membrane bound RAGE for binding with AGEs and reduce the production of cytokines. It is hypothesized that low levels of serum sRAGE and esRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE would increase the levels of cytokines that would increase the levels MMPs, thus contributing to the formation of TAAs.

Methods: The study population was composed of 17 control subjects and 20 patients with TAA. Blood samples were collected for measurement of serum sRAGE, esRAGE, AGEs, cytokines, and MMPs. AGEs, sRAGE, and esRAGE were measured using ELISA kits, whereas the remaining parameters were measured using the Luminex Multi-Analyte system.

Results: The levels of sRAGE were lower, while the levels of AGEs, AGEs/sRAGE, AGEs/esRAGE, cytokines and MMPs were higher in patients with TAA compared to controls. The levels of sRAGE were inversely correlated with cytokines and MMPs, while AGEs, AGEs/sRAGE and AGEs/esRAGE were positively correlated with cytokines and MMPs. Cytokines were positively correlated with MMPs.

Conclusions: The data suggest that the AGE-RAGE axis may be involved in the pathogenesis of TAA and that low levels of sRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE are risk factors for TAA.

 
  • References

  • 1 Kotze CW, Ahmad IG. Etiology and pathology of aortic aneurysm. In: Grundmann R. Etiology, pathogenesis and pathophysiology of aortic aneurysms and aneurysmal rupture. July 2011. , pp. 1-31 . DOI: 10.5772/18257
  • 2 DiMusto PD, Upchurch GR. The pathogenesis of abdominal aortic aneurysms. Available at http://admin.vascularweb.org/research/Pages/the-pathogenesis-of-abdominal-aortic-aneurysms.aspx . Accessed on November, 2014.
  • 3 Mountain DJ, Singh M, Menon B, Singh K. Interleukin-1 beta increases expression of activity of matrix metalloproteinase-2 in cardiac microvascular endothelial cells: Role of PKC alpha/beta 1 and MAPKs. Am J Physiol Cell Physiol 2007; 292: C867-C875 . DOI: 10.1152/ajpcell.00161.2006
  • 4 Wong W-R, Kossodo S, Kochevar IE. Influence of cytokines on matrix metalloproteinases produced by fibroblasts cultured in monolayer and collagen gells. J Formos Med Assoc 2001; 100: 377-382 . PMID: 11480246
  • 5 Edsparr K, Speetjens FM, Mulder-Stapel A, Goldfarb RH, Basse PH, Lennermas B. , et al. Effects of IL-2 on MMP expression in freshly isolated human NK cells and the IL-2-independent NK cell line YT. J Immunother 2010; 33: 475-481 . DOI: 10.1097/CJI.0b013e3181d372a0
  • 6 Kusano K, Miyaura C, Inda M, Tamura T, Ito A, Nagase H. , et al. Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: Association of MMP induction with bone reabsorption. Endocrinology 1998; 139: 1338-1345 . DOI: 10.1210/endo.139.3.5818#sthash.BIYPY8aH.dpuf
  • 7 Bucala R, Cerami A. Advanced glycosylation: Chemistry, biology, and implications for diabetes and aging. Adv Pharmacol 1992; 23: 1-34 . DOI: 10.1016/S1054-3589(08)60961-8
  • 8 Prasad K. Soluble receptor for advanced glycation end products (sRAGE) and cardiovascular disease. Int J Angiol 2006; 15: 57-68
  • 9 Hoffman MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y. , et al. RAGE mediates a novel proinflammatory axis: A central surface receptor for S100/ calgranulin polypeptides. Cell 1999; 97: 889-901 . DOI: 10.1016/S0092-8674(00)80801-6
  • 10 Lappas M, Permezel M, Rice G. Advanced glycation end products mediate pro-inflammatory actions in human gestational tissues via nuclear factor-κB and extracellular signal-regulated kinase 1/2. J Endocrinol 2007; 193: 269-277 . DOI: 10.1677/JOE-06-0081
  • 11 Schmidt AM, Yan SD, Yan SF, Stern DM. The biology of receptor for advanced glycation end products and its ligands. Biochem Biophys Acta 2000; 1498: 99-111 . DOI: 10.1016/S0167-4889(00)00087-2
  • 12 Tam XHL, Shiu SWM, Leng L, Bucala R, Betteridge DJ, Tan KCB. Enhanced expression of receptor for advanced glycation end-products is associated with low circulating soluble isoforms of the receptors in Type 2 diabetes. Clin Sci 2011; 120: 81-89 . DOI: 10.1042/CS20100256
  • 13 Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H. 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: 1097-1109 . DOI: 10.1042/bj20021371
  • 14 Geroldi D, Falcone C, Emanuele E. Soluble receptor for advanced glycation end products: from disease marker to potential therapeutic target. Current Med Chem 2006; 13: 1971-1978 . DOI: 10.2174/092986706777585013
  • 15 Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 2001; 280: C53-C60 . PMID: 11121376
  • 16 Sarkar A, Prasad K, Ziganshin BA, Elefteriades JA. Reasons to investigate the soluble receptor for advanced glycation end products (sRAGE) pathway in aortic disease. Aorta (Stamford) 2013; 1: 210-217 . DOI: 10.12945/j.aorta.2013.13-047
  • 17 Fulton RJ, McDade RL, Smith PL, Keinker LJ, Kettman Jr JR. Advanced multiplexed analysis with the FlowMetrix system. Clin Chem 1997; 43: 1749-1756 . PMID: 9299971
  • 18 Martins TB, Pasi BM, Pickering JW, Jaskowski TD, Litwin CM, Hill HR. Determination of cytokine responses using a multiplexed fluorescent microsphere immunoassay. Am J Clin Pathol 2002; 118: 346-353 . DOI: 10.1309/N0T6-C56B-GXB2-NVFB
  • 19 Juvonen I, Surcel HM, Satta J, Teppo AM, Bloiqu A, Syrialo H. , et al. Elevated circulating levels of inflammatory cytokines in patients with abdominal aortic aneurysm. Arterioscler Throm Vasc Biol 1997; 17: 2843-2847 . DOI: 10.1161/01.ATV.17.11.2843
  • 20 Rohde LE, Arroyo LH, Rifai N, Creager MA, Libby P, Ridker PM. , et al. Plasma concentrations of interleukin-6 and abdominal aortic diameter among subjects without aortic dilatation. Arterioscler Throm Vasc Biol 1999; 19: 1695-1699 . DOI: 10.1161/01.ATV.19.7.1695
  • 21 Jones KG, Brull DJ, Brown LC, Sian M, Greenhalgh RM, Humphries SE. , et al. Interleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms. Circulation 2001; 103: 2260-2265 . DOI: 10.1161/01.CIR.103.18.2260
  • 22 Karapanagiotidis GT, Antonitsis P, Charokopos N, Foroulis N, Anastasiadis K, Rouska E. , et al. Serum levels of matrix metalloproteinases-1, -2, -3, and -9 in thoracic diseases and acute myocardial ischemia. J Cardiothorac Surg 2009; 4: 59 . DOI: 10.1186/1749-8090-4-59
  • 23 Simova J, Skvor J, Reissigova J, Dudra J, Lindner J, Capek P. , et al. Serum levels of matrix metalloproteinases 2 and 9 and TGFBR2 gene screening in patients with ascending aortic dilatation. Folia Biologica (Praha) 2013; 59: 154-161
  • 24 Nordon IM, Hinchliffe RJ, Holt PJ, Loftus IM, Thompson MM. Review of current theories for abdominal aortic aneurysm pathogenesis. Vascular 2009; 17: 253-263 . DOI: 10.2310/6670.2009.00046
  • 25 McMillan WE, Pearce WH. Increased plasma levels of metalloproteinase-9 are associated with abdominal aortic aneurysms. J Vasc Surg 1999; 29: 122-127 . DOI: 10.1016/S0741-5214(99)70363-0