EDITORIAL FOCUSEndothelial dysfunction and vascular inflammation in Type 2 diabetes: interaction of AGE/RAGE and TNF-α signalingAnna Csiszar, and Zoltan UngvariAnna Csiszar, and Zoltan UngvariPublished Online:01 Aug 2008https://doi.org/10.1152/ajpheart.00644.2008This is the final version - click for previous versionMoreSectionsPDF (40 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations the receptor for advanced glycation end products (RAGE) interacts with a diverse range of endogenous ligands termed advanced glycation end products (AGEs), which are formed by the Maillard reaction, a nonenzymatic process linking reducing sugar groups to proteins, lipids, and nucleic acids. AGEs form in vivo in hyperglycemic environments and during aging, and there is increasing evidence that AGE/RAGE signaling contributes to the pathophysiology of vascular disease in diabetes mellitus (for an excellent review, see Ref. 14).Role of AGE/RAGE and TNF-α in Diabetes-Associated Endothelial DysfunctionIn their article, Gao et al. (13) tested the hypothesis that impaired nitric oxide-dependent dilation in small coronary arteries in Type 2 diabetes results, in part, from elevated production of superoxide induced by the interaction of AGE/RAGE and TNF-α signaling. This study fits logically in a series of investigations from Zhang's laboratory, showing that increases in TNF expression in animal models of Type 2 diabetes induce the activation of NAD(P)H oxidase and the production of reactive oxidative species, leading to endothelial dysfunction (12, 19). These data also indicate that vascular TNF-α expression and NF-κB induction increase in Type 2 diabetes that could be attenuated by anti-TNF-α treatment or the administration of the soluble form of RAGE (sRAGE) (12, 13). In the present article, the authors show that Type 2 diabetic mouse expression of RAGE in coronary arterioles was markedly increased and that activation of RAGE with RAGE agonist S100b (11) impaired endothelium-mediated vasorelaxation (13). Based on the findings that sRAGE or NF-κB inhibitor MG132-attenuated TNF-α expression, the authors present the hypothesis that in the coronary arteries of diabetic mice, AGE/RAGE signaling activates NF-κB, which contributes, at least in part, to the upregulation of TNF-α. This is an intriguing hypothesis, since it clearly points to the existence of a feed-forward loop that amplifies the initial signal and further enhances vascular inflammation in diabetes. The proposed hypothesis is supported by earlier observations (3, 21). For example, the promoter region of the TNF-α gene contains a NF-κB binding element, and the ligation of RAGE is known to trigger a series of cellular signaling events, including the activation of NF-κB, leading to the production of proinflammatory cytokines (14). It is also important to note that the expression of RAGE itself is also controlled by NF-κB (17, 24). TNF-α is known to induce NAD(P)H oxidase-dependent O2− generation (5, 22), and the authors have previously shown that both TNF-α antagonists (12, 19) and sRAGE inhibit the expression/activity of NAD(P)H oxidases in Type 2 diabetic mice (13).Implications for Diabetic Vasculopathy and Vascular AgingTaken together, the findings in the report of Gao et al. (13) show for the first time how AGE/RAGE signaling plays a pivotal role in regulating the production/expression of TNF-α, oxidative stress, and endothelial dysfunction in the coronary vasculature in Type 2 diabetes. In addition to the proposed pathway, AGEs may also regulate monocyte migration and adhesion, endothelial permeability, and modulate blood coagulation pathways (2, 4, 10, 14, 20). A continued examination of the role of AGE/RAGE in cardiovascular disease and accelerated vascular aging is expected to lead to the discovery of new pathways and the design of new treatment modalities for inhibiting low-grade inflammation in the vessel wall, preventing the development of vascular disease in Type 2 diabetes. In this regard, it is interesting that AGEs are also formed during aging and that vascular aging is also characterized by NF-κB activation (23), upregulation of TNF-α (6–8), NAD(P)H oxidase activation (6), and endothelial dysfunction (5). Thus further studies are definitely needed to elucidate the role of AGE/RAGE signaling in low-grade vascular inflammation and oxidative stress in aging as well.Clinical ImplicationsA variety of different compounds that inhibit AGE formation has been under investigation for the prevention of diabetic complications (14). Aminoguanidine is a hydrazine compound that prevents AGE formation (9), and there are studies extant suggesting that it favorably affects vascular structure and function in experimental models of diabetes (14). Structurally different inhibitors of AGE-induced cross-links (e.g., ALT-946, OPB-9195, and ALT-711) also elicit significant improvement of cardiovascular function in diabetes (1, 14). AGE levels can also be reduced through dietary modifications (16). Another therapeutical option is the blockade of RAGE by sRAGE. Extensive laboratory studies from Zhang's laboratory and others (15, 18) suggest that sRAGE may be an effective intervention against diabetes-induced atherosclerosis and coronary dysfunction. Future clinical studies are evidently needed to test the potential impact of RAGE blockade on coronary arterial function in human subjects.GRANTSThis publication was supported by National Heart, Lung, and Blood Institute Grants HL-077256 and HL-43023.REFERENCES1 Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 97: 2809–2813, 2000.Crossref | PubMed | ISI | Google Scholar2 Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, Kislinger T, Stern DM, Schmidt AM, De Caterina R. 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Ungvari, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByMiR-27b attenuates mitochondrial oxidative stress and inflammation in endothelial cellsRedox Biology, Vol. 62Role of peroxisome proliferators-activated receptor-gamma in advanced glycation end product-mediated functional loss of voltage-gated potassium channel in rat coronary arteries14 July 2020 | BMC Cardiovascular Disorders, Vol. 20, No. 1Molecular Mechanism of the Effect of Huanglian Jiedu Decoction on Type 2 Diabetes Mellitus Based on Network Pharmacology and Molecular DockingJournal of Diabetes Research, Vol. 2020Ly6C + Inflammatory Monocyte Differentiation Partially Mediates Hyperhomocysteinemia-Induced Vascular Dysfunction in Type 2 Diabetic db/db MiceArteriosclerosis, Thrombosis, and Vascular Biology, Vol. 39, No. 10Biomarkers of Oxidative Stress in Metabolic Syndrome and Associated DiseasesOxidative Medicine and Cellular Longevity, Vol. 2019Chronic inhibition of lipoprotein-associated phospholipase A2 does not improve coronary endothelial function: A prospective, randomized-controlled trialInternational Journal of Cardiology, Vol. 253Productos finales de glicación avanzada en la enfermedad cardiovascular como complicación de la diabetesMedicina e Investigación, Vol. 4, No. 1Mouse Models of Calcific Aortic Valve Disease22 March 2014Inhibitory Effect of Gallic Acid on Advanced Glycation End Products Induced Up-Regulation of Inflammatory Cytokines and Matrix Proteins in H9C2 (2-1) Cells24 September 2013 | Cardiovascular Toxicology, Vol. 13, No. 4Toxicity features of high glucose on endothelial cell cycle and protection by Dan Gua-Fang (丹瓜方) in ECV-304 in high glucose medium9 February 2012 | Chinese Journal of Integrative Medicine, Vol. 19, No. 8Hydrogen-rich medium suppresses the generation of reactive oxygen species, elevates the Bcl-2/Bax ratio and inhibits advanced glycation end product-induced apoptosis5 April 2013 | International Journal of Molecular Medicine, Vol. 31, No. 6Advanced glycation end products-induced reactive oxygen species generation is partly through NF-kappa B activation in human aortic endothelial cellsJournal of Diabetes and its Complications, Vol. 27, No. 1Oxidant stress and skeletal muscle microvasculopathy in the metabolic syndromeVascular Pharmacology, Vol. 57, No. 5-6Preventative Effects of 4,4'-Diphenylmethane-bis(methyl) Carbamate Isolated from Cortex Mori on Human Umbilical Vein Endothelial Cell Dysfunction Induced by Advanced Glycation End Products28 July 2011 | Phytotherapy Research, Vol. 26, No. 3Association between sRAGE, esRAGE levels and vascular inflammation: Analysis with 18F-fluorodeoxyglucose positron emission tomographyAtherosclerosis, Vol. 220, No. 2Protective Effects of Danggui Buxue Tang on a Human Umbilical Vein Endothelialcell Damage Induced by Advanced Glycation End ProductsPharmacology & Pharmacy, Vol. 03, No. 02Knockdown of RAGE expression inhibits colorectal cancer cell invasion and suppresses angiogenesis in vitro and in vivoCancer Letters, Vol. 313, No. 1Rosiglitazone Attenuates Endothelial Progenitor Cell Apoptosis Induced by TNF-α via ERK/MAPK and NF-κB Signal PathwaysJournal of Pharmacological Sciences, Vol. 117, No. 4Chinese prescription Kangen-karyu prevents dyslipidaemia and oxidative stress in mouse model of type 2 diabetes11 October 2010 | Journal of Pharmacy and Pharmacology, Vol. 63, No. 1Hypolipidaemic and antioxidative effects of oligonol, a low-molecular-weight polyphenol derived from lychee fruit, on renal damage in type 2 diabetic mice20 July 2010 | British Journal of Nutrition, Vol. 104, No. 8Rosiglitazone via upregulation of Akt/eNOS pathways attenuates dysfunction of endothelial progenitor cells, induced by advanced glycation end products16 November 2009 | British Journal of Pharmacology, Vol. 158, No. 8Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling28 January 2009 | Cardiovascular Research, Vol. 82, No. 1Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular DamageDiabetes, Vol. 58, No. 1 More from this issue > Volume 295Issue 2August 2008Pages H475-H476 Copyright & PermissionsCopyright © 2008 by the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00644.2008PubMed18599592History Published online 1 August 2008 Published in print 1 August 2008 Metrics