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