Closing the Loop on RAGE Periodontal Disease and Vascular Inflammation

These data highlight the concept that a key common denominator in infected periodontium and diabetic blood vessels is enhanced inflammation. Our findings on the role of RAGE blockade in attenuating inflammation and tissue injury in both settings place RAGE at the center of a cascade of systemic/local inflammatory conditions that may accelerate microvascular dysfunction. We thus propose that peri-odontal disease presents a sufficient stimulus to augment both local and systemic vascular activation—processes that, if left unchecked, may predispose to acceleration of atherosclerosis. In the setting of diabetes, however, inflammation in local and vascular tissues is further fueled, at least in part via ligation of RAGE, by accumulation of AGEs, proin-flammatory molecules such as S100/calgranulins, and oxi-dant species.

Taken together, these considerations underscore the premise that control of the exaggerated inflammatory response in bacterial infection of the periodontium and in the diabetic vessel wall may provide therapeutic benefit in vascular disease and atherosclerosis.

Glossary

Advanced glycation end products: Products of nonenzymatic glyca-tion and oxidation of proteins and lipids; these species may be formed by such stimuli as hyperglycemia, inflammation, and oxidant stress.

Flow-mediated dilation: Measure of endothelial function and the bioavailability/activity of nitric oxide; flow-mediated dilation is generally measured by assessment of blood flow in the brachial artery by ultrasonography.

Periodontium: The tissues that invest and support the teeth including the gingiva, cementum (covering the roots), alveolar bone, and periodontal ligament (the ligament that attaches the tooth to the bone).

References

1. Beck, J. D., and Offenbacher, S. (2001). The association between periodontal diseases and cardiovascular diseases: A state-of-the-science review. Ann. Periodontol. 6, 9-15. A review of the evidence for an association between cardiovascular and periodontal diseases.

2. De Nardin, E. (2001). The role of inflammatory and immunological mediators in periodontitis and cardiovascular disease. Ann. Periodontol. 6, 30-40. A comprehensive review of host-related mechanisms that may explain the association between cardiovascular and periodontal diseases.

3. Beck, J. D., Elter, J. R., Heiss, G., Couper, D., Mauriello, S. M., and Offenbacher, S. (2001). Relationship of periodontal disease to carotid artery intima-media wall thickness: The atherosclerosis risk in communities (ARIC) study. Arterioscler. Thromb. Vasc. Biol. 21, 1816-1822.

4. Desvarieux, M., Demmer, R. T., Rundek, T., Boden-Albala, B., Jacobs, D.R., Jr., Papapanou, P. N., and Sacco, R. L. (2003). Relationship between periodontal disease, tooth loss, and carotid artery plaque: The Oral Infections and Vascular Disease Epidemiology Study (INVEST). Stroke 34, 2120-2125.

5. Li, L., Messas, E., Batista, E. L., Jr., Levine, R. A., and Amar, S. (2002). Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model. Circulation 105, 861-867.

6. Park, L., Raman, K. G., Lee, K. J., Lu, Y., Ferran, L. J., Jr., Chow, W.S., Stern, D., and Schmidt, A. M. (1998). Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation end-products. Nat. Med. 4, 1025-1031.

7. Bucciarelli, L. G., Wendt, T., Qu, W., Lu, Y., Lalla, E., Rong, L. L., Goova, M. T., Moser, B., Kislinger, T., Lee, D. C., Kashyap, Y., Stern, D. M., and Schmidt, A. M. (2002). RAGE blockade stabilizes estab lished atherosclerosis in diabetic apolipoprotein E-null mice. Circulation 106, 2827-2835.

Further Reading

Amar, S., Gokce, N., Morgan, S., Loukideli, M., Van Dyke, T. E., and Vita, J. A. (2003). Periodontal disease is associated with brachial artery endothelial dysfunction and systemic inflammation. Arterioscler. Thromb. Vasc. Biol. 23, 1245-1249. The authors report that human subjects with severe periodontal disease exhibit endothelial dysfunction (decreased flow-mediated dilation) and increased serum CRP.

Brevetti, G., Silvestro, A., Di Giacomo, S., Bucur, R., Di Donato, A., Schiano, V., and Scopacasa, F. (2003). Endothelial dysfunction in peripheral arterial disease is related to increase in plasma markers of inflammation and severity of peripheral circulatory impairment but not to classic risk factors and atherosclerotic burden. J. Vasc. Surg. 38, 374-379.

Lalla, E., Lamster, I. B., Feit, M., Huang, L., and Schmidt, A. M. (1998). A murine model of accelerated periodontal disease in diabetes. J. Peri-odont. Res. 33, 387-399.

Lalla, E., Lamster, I. B., Feit, M., Huang, L., Spessot, A., Qu, W., Kislinger, T., Lu, Y., Stern, D. M., and Schmidt, A. M. (2000). Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice. J. Clin. Invest. 105, 1117-1124.

Lalla, E., Lamster, I. B., Hofmann, M. A., Bucciarelli, L., Jerud, A. P., Tucker, S., Lu, Y., Papapanou, P. N., and Schmidt, A. M. (2003). Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein e-null mice. Arterioscler. Thromb. Vasc. Biol. 23, 1405-1411.

Manson, J. E., Hsia, J., Johnson, K. C., Rossouw, J. E., Assaf, A. R., Lasser, N. L., Trevisan, M., Black, H. R., Heckbert, S. R., Detrano, R., Strickland, O. L., Wong, N. D., Crouse, J. R., Stein, E., and Cushman,

M. (2003). Estrogen plus progestin and the risk of coronary heart disease. N. Engl. J. Med. 349, 523-534.

Sitges, M., Heras, M., Roig, E., Duran, M., Masotti, M., Zurbano, M. J., Roque, M., and Sanz, G. (2001). Acute and mid-term combined hormone replacement therapy improves endothelial function in postmenopausal women with angina and angiographically normal coronary arteries. Eur. Heart J. 22, 2116-2124.

Taylor, G. (2001). Bi-directional interrelationships between diabetes and periodontal diseases: An epidemiologic perspective. Ann. Periodontal. 6, 99-112. A comprehensive review of the evidence for the association between diabetes mellitus and periodontal diseases.

Yan, S. F., Ramasamy, R., Naka, Y., and Schmidt, A. M. (2003). Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond. Circ. Res. 93, 1159-1169. An overview of the role of the receptor for AGE in diabetes, atherosclerosis, and vascular dysfunction.

Capsule Biography

Evanthia Lalla, an Associate Professor of Dentistry at Columbia University, has been studying mechanisms underlying the association between diabetes, atherosclerosis, and periodontal infections.

Panos N. Papapanou and Ira B. Lamster are Professors of Dentistry at Columbia University and established investigators in the fields of epidemiology and pathogenesis of periodontal diseases.

Ann Marie Schmidt is a Professor of Surgery. Her laboratory primarily focuses on vascular biology and the receptor for advanced glycation end products.

Their work is supported by grants from the NIH, JDRFI, AHA, and Burroughs Wellcome Fund.

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