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EDITORIAL FOCUS
signalingDepartment of Physiology, New York Medical College, Valhalla, New York
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-
in Diabetes-Associated Endothelial Dysfunction
In 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- 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- expression and NF-
B induction increase in Type 2 diabetes that could be attenuated by anti-TNF- 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-B inhibitor MG132-attenuated TNF- expression, the authors present the hypothesis that in the coronary arteries of diabetic mice, AGE/RAGE signaling activates NF-B, which contributes, at least in part, to the upregulation of TNF-. 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- gene contains a NF-B binding element, and the ligation of RAGE is known to trigger a series of cellular signaling events, including the activation of NF-B, 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-B (17, 24). TNF- is known to induce NAD(P)H oxidase-dependent O2– generation (5, 22), and the authors have previously shown that both TNF- 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 Aging
Taken 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-, 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-B activation (23), upregulation of TNF- (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 Implications
A 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.
GRANTS
This publication was supported by National Heart, Lung, and Blood Institute Grants HL-077256 and HL-43023.
FOOTNOTES
Address for reprint requests and other correspondence: Z. Ungvari, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (e-mail: zoltan_ungvari{at}nymc.edu)
REFERENCES
treatment in aging. Am J Pathol 170: 388–698, 2007.B activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293: H37–H47, 2007.This article has been cited by other articles:
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  L. Gao and G. E. Mann Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling Cardiovasc Res, April 1, 2009; 82(1): 9 - 20. [Abstract] [Full Text] [PDF]
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 R. Arita, Y. Hata, S. Nakao, T. Kita, M. Miura, S. Kawahara, S. Zandi, L. Almulki, F. Tayyari, H. Shimokawa, et al. Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage Diabetes, January 1, 2009; 58(1): 215 - 226. [Abstract] [Full Text] [PDF]
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