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

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

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nature medicine publications

Nature Medicine 4, 1025 - 1031 (1998)
doi:10.1038/2012

Lisa Park1, 2, Kathleen G. Raman1, 2, Kenneth J. Lee1, 2, Yan Lu1, 2, Luis J. Ferran Jr.1, 2, Wing Sun Chow1, 2, David Stern1, 2 & Ann Marie Schmidt1, 3
1 Division of Surgical Science, Department of Surgery, Columbia University College of Physicians and Surgeons, New York , New York 10032, USA

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

3 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.

Correspondence should be addressed to Ann Marie Schmidt ams11@columbia.edu

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.

©1998 Nature Publishing Group