l-Citrulline and l-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits

Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13681-6. doi: 10.1073/pnas.0506595102. Epub 2005 Sep 12.


The objective of this study was to evaluate the influence of ingested l-arginine, l-citrulline, and antioxidants (vitamins C and E) on the progression of atherosclerosis in rabbits fed a high-cholesterol diet. The fatty diet caused a marked impairment of endothelium-dependent vasorelaxation in isolated thoracic aorta and blood flow in rabbit ear artery in vivo, the development of atheromatous lesions and increased superoxide anion production in thoracic aorta, and increased oxidation-sensitive gene expression [Elk-1 and phosphorylated cAMP response element-binding protein]. Rabbits were treated orally for 12 weeks with l-arginine, l-citrulline, and/or antioxidants. l-arginine plus l-citrulline, either alone or in combination with antioxidants, caused a marked improvement in endothelium-dependent vasorelaxation and blood flow, dramatic regression in atheromatous lesions, and decrease in superoxide production and oxidation-sensitive gene expression. These therapeutic effects were associated with concomitant increases in aortic endothelial NO synthase expression and plasma NO(2)(-)+NO(3)(-) and cGMP levels. These observations indicate that ingestion of certain NO-boosting substances, including l-arginine, l-citrulline, and antioxidants, can abrogate the state of oxidative stress and reverse the progression of atherosclerosis. This approach may have clinical utility in the treatment of atherosclerosis in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / administration & dosage
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Arginine / administration & dosage*
  • Arteriosclerosis / drug therapy
  • Arteriosclerosis / metabolism*
  • Arteriosclerosis / pathology
  • Ascorbic Acid / administration & dosage
  • Citrulline / administration & dosage*
  • Cyclic AMP Response Element-Binding Protein / biosynthesis
  • Cyclic GMP / metabolism
  • DNA-Binding Proteins / biosynthesis
  • Diet, Atherogenic*
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Humans
  • Male
  • Nitrates / metabolism
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase Type III
  • Nitrites / metabolism
  • Oxidation-Reduction / drug effects
  • Proto-Oncogene Proteins / biosynthesis
  • Rabbits
  • Superoxides / metabolism
  • Transcription Factors / biosynthesis
  • Vasodilation / drug effects
  • Vitamin E / administration & dosage
  • ets-Domain Protein Elk-1


  • Antioxidants
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • ELK1 protein, human
  • Nitrates
  • Nitrites
  • Proto-Oncogene Proteins
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Superoxides
  • Vitamin E
  • Citrulline
  • Arginine
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Cyclic GMP
  • Ascorbic Acid