title: Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice.
abstract: OBJECTIVE
  Atherosclerotic lesions are associated with the accumulation of reactive aldehydes derived from oxidized lipids. Although inhibition of aldehyde metabolism has been shown to exacerbate atherosclerosis and enhance the accumulation of aldehyde-modified proteins in atherosclerotic plaques, no therapeutic interventions have been devised to prevent aldehyde accumulation in atherosclerotic lesions.
  
  
  RESULTS
  We examined the efficacy of carnosine, a naturally occurring β-alanyl-histidine dipeptide, in preventing aldehyde toxicity and atherogenesis in apolipoprotein E-null mice. In vitro, carnosine reacted rapidly with lipid peroxidation-derived unsaturated aldehydes. Gas chromatography mass-spectrometry analysis showed that carnosine inhibits the formation of free aldehydes 4-hydroxynonenal and malonaldialdehyde in Cu(2+)-oxidized low-density lipoprotein. Preloading bone marrow-derived macrophages with cell-permeable carnosine analogs reduced 4-hydroxynonenal-induced apoptosis. Oral supplementation with octyl-D-carnosine decreased atherosclerotic lesion formation in aortic valves of apolipoprotein E-null mice and attenuated the accumulation of protein-acrolein, protein-4-hydroxyhexenal, and protein-4-hydroxynonenal adducts in atherosclerotic lesions, whereas urinary excretion of aldehydes as carnosine conjugates was increased.
  
  
  CONCLUSIONS
  The results of this study suggest that carnosine inhibits atherogenesis by facilitating aldehyde removal from atherosclerotic lesions. Endogenous levels of carnosine may be important determinants of atherosclerotic lesion formation, and treatment with carnosine or related peptides could be a useful therapy for the prevention or the treatment of atherosclerosis.
authors.affiliation: Diabetes and Obesity Center, School of Medicine, University of Louisville, Louisville, KY 40202, USA. o.barski@louisville.edu
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Barski
authors.forename: Zhengzhi
authors.initials: Z
authors.lastname: Xie
authors.forename: Shahid P
authors.initials: SP
authors.lastname: Baba
authors.forename: Srinivas D
authors.initials: SD
authors.lastname: Sithu
authors.forename: Abhinav
authors.initials: A
authors.lastname: Agarwal
authors.forename: Jian
authors.initials: J
authors.lastname: Cai
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000517:prevention & control*; D002336:Carnosine / Q000494:pharmacology*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D015227:Lipid Peroxidation / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011897:Random Allocation; D012016:Reference Values
chemical_list: D000447:Aldehydes; D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D002336:Carnosine
keywords: aldehydes; atherosclerosis; carnosine; oxidized low-density lipoprotein
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