Human Aldose Reductase Expression Accelerates Diabetic Atherosclerosis in
Transgenic Mice
Authors Reeba K. Vikramadithyan, Yunying Hu, Hye-Lim Noh, Chien-Ping Liang, Kellie
Hallam, Alan R. Tall, Ravichandran Ramasamy and Ira J. Goldberg
Submitted By Ira Goldberg on 7/15/2005
Status Published
Journal The Journal of clinical investigation
Year 2005
Date Published 9/1/2005
Volume : Pages 115 : 2434 - 2443
PubMed Reference 16127462
Abstract Direct evidence that hyperglycemia, rather than concomitant increases in known
risk factors, induces atherosclerosis is lacking. Most diabetic mice do not have
greater amounts of atherosclerosis unless the development of diabetes is
associated with more severe hyperlipidemia. We hypothesized that normal mice
were deficient in a gene that accelerated atherosclerosis with diabetes. Aldose
reductase (AR), a gene that mediates the generation of toxic products from
glucose, is expressed at low levels in murine compared to human tissues.
Streptozotocin (STZ)-treated, but not non-diabetic, mice expressing human AR
(hAR) crossed with LDL receptor deficient (Ldlr-/-) C57BL/6 male mice had
increased aortic atherosclerosis. Diabetic hAR-expressing heterozygous LDL
receptor knockout mice (Ldlr+/-) fed a cholesterol cholic acid-containing diet
also had increased aortic lesion size. Lesion area at the aortic root was
increased by STZ treatment alone, but this was further increased by hAR
expression. Macrophages from hAR-transgenic mice expressed more scavenger
receptors and had greater accumulation of modified lipoproteins. Genes that
regulate regeneration of glutathione were reduced in the hAR-expressing aortas.
Thus, hAR increases atherosclerosis in diabetic mice. Inhibitors of AR or other
enzymes that mediate glucose toxicity could be useful therapy for diabetic


Akr1b3aldo-keto reductase family 1, member B3 (aldose reductase)
Akr1b7aldo-keto reductase family 1, member B7
Arandrogen receptor
Fdxrferredoxin reductase
Akr1b8aldo-keto reductase family 1, member B8
Cyp19a1cytochrome P450, family 19, subfamily a, polypeptide 1