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Publication

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 atherosclerosis.

Complications
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Genes
Symbol Description Akr1b3 aldo-keto reductase family 1, member B3 (aldose reductase) Akr1b7 aldo-keto reductase family 1, member B7 Ar androgen receptor Areg amphiregulin Fdxr ferredoxin reductase Akr1b8 aldo-keto reductase family 1, member B8 Cyp19a1 cytochrome P450, family 19, subfamily a, polypeptide 1