title: Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction.
abstract: The nitrite anion is an endogenous product of mammalian nitric oxide (NO) metabolism, a key intermediate in the nitrogen cycle in plants, and a constituent of many foods. Research over the past 6 years has revealed surprising biological and cytoprotective activity of this anion. Hypercholesterolemia causes a proinflammatory phenotype in the microcirculation. This phenotype appears to result from a decline in NO bioavailability that results from a reduction in NO biosynthesis, inactivation of NO by superoxide, or both. Since nitrite has been shown to be potently cytoprotective and restore NO biochemical homeostasis, we investigated if supplemental nitrite could attenuate microvascular inflammation caused by a high cholesterol diet. C57Bl/6J mice were fed either a normal diet or a high cholesterol diet for 3 wk to induce microvascular inflammation. Mice on the high cholesterol diet received either nitrite-free drinking water or supplemental nitrite at 33 or 99 mg/l ad libitum in their drinking water. The results from this investigation reveal that mice fed a cholesterol-enriched diet exhibited significantly elevated leukocyte adhesion to and emigration through the venular endothelium as well as impaired endothelium-dependent relaxation in arterioles. Administration of nitrite in the drinking water inhibited the leukocyte adhesion and emigration and prevented the arteriolar dysfunction. This was associated with sparing of reduced tetrahydrobiopterin and decreased levels of C-reactive protein. These data reveal novel anti-inflammatory properties of nitrite and implicate the use of nitrite as a new natural therapy for microvascular inflammation and endothelial dysfunction associated with hypercholesterolemia.
authors.affiliation: Department of Molecular and Cellular Physiology, Brown Foundation Institute of Molecular Medicine, The Univ. of Texas-Houston Health Science Center, 1825 Pressler St., SRB 530B, Houston, TX 77030, USA.
authors.forename: Karen Y
authors.initials: KY
authors.lastname: Stokes
authors.forename: Tammy R
authors.initials: TR
authors.lastname: Dugas
authors.forename: Yaoping
authors.initials: Y
authors.lastname: Tang
authors.forename: Harsha
authors.initials: H
authors.lastname: Garg
authors.forename: Eric
authors.initials: E
authors.lastname: Guidry
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Bryan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002097:C-Reactive Protein / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000097:blood; D004032:Diet; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D036904:Leukocyte Rolling / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D012977:Sodium Nitrite / Q000008:administration & dosage* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D002791:Cholesterol, Dietary; D014280:Triglycerides; D014665:Vasodilator Agents; D001708:Biopterins; D009569:Nitric Oxide; D002097:C-Reactive Protein; C003402:sapropterin; D012977:Sodium Nitrite