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

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...

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Published inNature medicine Vol. 4; no. 9; pp. 1025 - 1031
Main Authors Schmidt, Ann Marie, Park, Lisa, Raman, Kathleen G, Lee, Kenneth J, Lu, Yan, Ferran, Luis J, Chow, Wing Sun, Stern, David
Format Journal Article
LanguageEnglish
Published United States 01.09.1998
Subjects
Animals
Arteriosclerosis - drug therapy
Arteriosclerosis - etiology
Cell Line
Diabetes Mellitus, Experimental - complications
Diabetes Mellitus, Experimental - physiopathology
Diabetic Angiopathies - drug therapy
Glycation End Products, Advanced - metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Receptor for Advanced Glycation End Products
Receptors, Immunologic - metabolism
Receptors, Immunologic - therapeutic use
Recombinant Fusion Proteins - metabolism
Solubility
Spodoptera
Streptozocin
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Summary: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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ISSN:1078-8956
1546-170X
DOI:10.1038/2012