Nitric oxide and arginine dysregulation: A novel pathway to pulmonary hypertension in hemolytic disorders

Claudia R. Morris, Mark T. Gladwin, Gregory J. Kato

Research output: Contribution to journalReview articlepeer-review


Secondary pulmonary hypertension (PH) is emerging as one of the leading causes of mortality and morbidity in patients with hemolytic anemias such as sickle cell disease (SCD) and thalassemia. Impaired nitric oxide (NO) bioavailability represents the central feature of endothelial dysfunction, and is a major factor in the pathophysiology of PH. Inactivation of NO correlates with hemolytic rate and is associated with the erythrocyte release of cell-free hemoglobin, which consumes NO directly, and the simultaneous release of the arginine-metabolizing enzyme arginase, which limits bioavailability of the NO synthase substrate arginine during the process of intravascular hemolysis. Rapid consumption of NO is accelerated by oxygen radicals that exists in both SCD and thalassemia. A dysregulation of arginine metabolism contributes to endothelial dysfunction and PH in SCD, and is strongly associated with prospective patient mortality. The central mechanism responsible for this metabolic disorder is enhanced arginine turnover, occurring secondary to enhanced plasma arginase activity. This is consistent with a growing appreciation of the role of excessive arginase activity in human diseases, including asthma and pulmonary arterial hypertension. New treatments aimed at improving arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, oral arginine supplementation, or use of NO donors represent potential therapeutic strategies for this common pulmonary complication of hemolytic disorders.

Original languageEnglish (US)
Pages (from-to)620-632
Number of pages13
JournalCurrent Molecular Medicine
Issue number7
StatePublished - 2008
Externally publishedYes


  • Arginase
  • Arginine
  • Hemoglobinopathies
  • Hemolysis
  • Nitric oxide
  • Pulmonary hypertension
  • Sickle cell disease
  • Thalassemia

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology


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