title: Aldose reductase protects against early atherosclerotic lesion formation in apolipoprotein E-null mice.
abstract: BACKGROUND
  Atherosclerotic lesion formation is associated with the accumulation of oxidized lipids. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion; however, their contribution to atherosclerotic lesion formation remains unclear.
  
  
  OBJECTIVE
  To test the hypothesis that inhibition of aldehyde removal by aldose reductase (AR), which metabolizes both free and phospholipid aldehydes, exacerbates atherosclerotic lesion formation.
  
  
  RESULTS
  In atherosclerotic lesions of apolipoprotein (apo)E-null mice, AR protein was located in macrophage-rich regions and its abundance increased with lesion progression. Treatment of apoE-null mice with AR inhibitors sorbinil or tolrestat increased early lesion formation but did not affect the formation of advanced lesions. Early lesions of AR(-/-)/apoE(-/-) mice maintained on high-fat diet were significantly larger when compared with age-matched AR(+/+)/apoE(-/-) mice. The increase in lesion area attributable to deletion of the AR gene was seen in both male and female mice. Pharmacological inhibition or genetic ablation of AR also increased the lesion formation in male mice made diabetic by streptozotocin treatment. Lesions in AR(-/-)/apoE(-/-) mice exhibited increased collagen and macrophage content and a decrease in smooth muscle cells. AR(-/-)/apoE(-/-) mice displayed a greater accumulation of the AR substrate 4-hydroxy trans-2-nonenal (HNE) in the plasma and protein-HNE adducts in arterial lesions than AR(+/+)/apoE(-/-) mice.
  
  
  CONCLUSIONS
  These observations indicate that AR is upregulated in atherosclerotic lesions and it protects against early stages of atherogenesis by removing toxic aldehydes generated in oxidized lipids.
authors.affiliation: Diabetes and Obesity Center, Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, USA. sanjay@louisville.edu
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.forename: Elena
authors.initials: E
authors.lastname: Vladykovskaya
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Barski
authors.forename: Matthew
authors.initials: M
authors.lastname: Spite
authors.forename: Karin
authors.initials: K
authors.lastname: Kaiserova
authors.forename: J Mark
authors.initials: JM
authors.lastname: Petrash
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Chung
authors.forename: Greg
authors.initials: G
authors.lastname: Hunt
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D048289:Imidazolidines / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D009281:Naphthalenes / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000447:Aldehydes; D001057:Apolipoproteins E; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D009281:Naphthalenes; D010743:Phospholipids; C040550:tolrestat; D000449:Aldehyde Reductase; C026411:sorbinil