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Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts

Nature Medicine volume 4, pages 1025–1031 (1998)Cite this article

Abstract

Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.

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Figure 1: Accelerated atherosclerosis in diabetic apoE-null mice.
Figure 2: Analysis of possible contributory factors underlying accelerated diabetic atherosclerosis.
Figure 3: sRAGE suppresses accelerated diabetic atherosclerosis.
Figure 4: Analysis of potential contributory factors underlying the beneficial effects of sRAGE in suppressing accelerated diabetic atherosclerosis.

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Acknowledgements

The authors acknowledge the advice and assistance of N. Maeda, E. Rubin, C. Fu, W. Qu, J. Verstuyft, S. Drury and E. Bernstein. We thank M. Prescott, G. Andres and G.C. Godman for their suggestions and review of the histology. This work was supported by grants from the USPHS (AG00602, DK52495 and HL 56881), the American Heart Association, New York City affiliate, the Council for Tobacco Research, the Juvenile Diabetes Foundation and the Surgical Research Fund.

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  1. Ann Marie Schmidt: Department of Medicine Columbia University College of Physicians and Surgeons, New York, New York 10032, USA L.P. and K.R. contributed equally to this work.

Authors and Affiliations

  1. Division of Surgical Science, Department of Surgery Columbia University College of Physicians and Surgeons, New York , 10032, New York, USA

    Lisa Park, Kathleen G. Raman, Kenneth J. Lee, Yan Lu, Luis J. Ferran Jr., Wing Sun Chow, David Stern & Ann Marie Schmidt

  2. Department of Physiology Columbia University College of Physicians and Surgeons, New York, 10032, New York, USA

    Lisa Park, Kathleen G. Raman, Kenneth J. Lee, Yan Lu, Luis J. Ferran Jr., Wing Sun Chow & David Stern

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Correspondence to Ann Marie Schmidt.

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Park, L., Raman, K., Lee, K. et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med 4, 1025–1031 (1998). https://doi.org/10.1038/2012

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