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

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 [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{N}{O}₂⁻+{N}{O}₃⁻{equation*}{document} 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.