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 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.
Park
L
L
Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Raman
K G
KG
Lee
K J
KJ
Lu
Y
Y
Ferran
L J
LJ
Chow
W S
WS
Stern
D
D
Schmidt
A M
AM
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012995:Solubility; D018411:Spodoptera; D013311:Streptozocin
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D013311:Streptozocin