Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilators, hemolysis, and oxidative stress

Am J Physiol Heart Circ Physiol. 2008 Jul;295(1):H39-47. doi: 10.1152/ajpheart.00162.2008. Epub 2008 May 2.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcholine / pharmacology
  • Anemia, Sickle Cell / drug therapy*
  • Anemia, Sickle Cell / genetics
  • Anemia, Sickle Cell / metabolism
  • Anemia, Sickle Cell / physiopathology
  • Animals
  • Arginine / pharmacology*
  • Citrulline / blood
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Globins / genetics
  • Globins / metabolism
  • Heme Oxygenase-1 / metabolism
  • Hemodynamics / drug effects
  • Hemoglobins / metabolism
  • Hemolysis / drug effects*
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microcirculation / drug effects
  • Microcirculation / metabolism
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / blood
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / pharmacology*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / metabolism
  • Nitric Oxide Synthase Type III
  • Nitroprusside / pharmacology
  • Oxidative Stress / drug effects*
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Vasodilator Agents / metabolism
  • Vasodilator Agents / pharmacology*

Substances

  • Enzyme Inhibitors
  • Hemoglobins
  • Membrane Proteins
  • Nitric Oxide Donors
  • Vasodilator Agents
  • Nitroprusside
  • Citrulline
  • Nitric Oxide
  • 3-nitrotyrosine
  • Tyrosine
  • Globins
  • Arginine
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Dinoprostone
  • Acetylcholine
  • NG-Nitroarginine Methyl Ester