title: Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilators, hemolysis, and oxidative stress.
abstract: In sickle cell disease, nitric oxide (NO) depletion by cell-free plasma hemoglobin and/or oxygen radicals is associated with arginine deficiency, impaired NO bioavailability, and chronic oxidative stress. In transgenic-knockout sickle (BERK) mice that express exclusively human alpha- and beta(S)-globins, reduced NO bioavailability is associated with induction of non-NO vasodilator enzyme, cyclooxygenase (COX)-2, and impaired NO-mediated vascular reactivity. We hypothesized that enhanced NO bioavailability in sickle mice will abate activity of non-NO vasodilators, improve vascular reactivity, decrease hemolysis, and reduce oxidative stress. Arginine treatment of BERK mice (5% arginine in mouse chow for 15 days) significantly reduced expression of non-NO vasodilators COX-2 and heme oxygenase-1. The decreased COX-2 expression resulted in reduced prostaglandin E(2) (PGE(2)) levels. The reduced expression of non-NO vasodilators was associated with significantly decreased arteriolar dilation and markedly improved NO-mediated vascular reactivity. Arginine markedly decreased hemolysis and oxidative stress and enhanced NO bioavailability. Importantly, arteriolar diameter response to a NO donor (sodium nitroprusside) was strongly correlated with hemolytic rate (and nitrotyrosine formation), suggesting that the improved microvascular function was a response to reduced hemolysis. These results provide a strong rationale for therapeutic use of arginine in sickle cell disease and other hemolytic diseases.
authors.affiliation: Dept. of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. kaul@aecom.yu.edu
authors.forename: Dhananjay K
authors.initials: DK
authors.lastname: Kaul
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Zhang
authors.forename: Trisha
authors.initials: T
authors.lastname: Dasgupta
authors.forename: Mary E
authors.initials: ME
authors.lastname: Fabry
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D002956:Citrulline / Q000097:blood; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005914:Globins / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D006454:Hemoglobins; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009599:Nitroprusside; D002956:Citrulline; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D005914:Globins; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester