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Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria

Yeo, T., Lampah, Daniel A., Gitawati, R., Tjitra, E., Kenangalem, Enny, Piera, Kim Alison, Price, Ric N., Duffull, S., Celermajer, David and Anstey, Nicholas M. (2008). Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proceedings of the National Academy of Sciences of USA,105(44):17097-17102.

Document type: Journal Article

IRMA ID 10247xPUB14
Title Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria
Author Yeo, T.
Lampah, Daniel A.
Gitawati, R.
Tjitra, E.
Kenangalem, Enny
Piera, Kim Alison
Price, Ric N.
Duffull, S.
Celermajer, David
Anstey, Nicholas M.
Journal Name Proceedings of the National Academy of Sciences of USA
Publication Date 2008
Volume Number 105
Issue Number 44
ISSN 0027-8424   (check CDU catalogue open catalogue search in new window)
Scopus ID 2-s2.0-55949108502
Start Page 17097
End Page 17102
Total Pages 6
Place of Publication US
Publisher National Academy of Sciences
Field of Research 1107 - Immunology
1108 - Medical Microbiology
1101 - Medical Biochemistry and Metabolomics
HERDC Category C1 - Journal Article (DEST)
Abstract Adherence of parasitized erythrocytes to activated endothelium causes microvascular obstruction, tissue ischemia, and clinical complications in severe malaria (SM); however, the mechanisms leading to endothelial activation remain unclear. The angiogenic factors, angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) are modulators of endothelial activation, with Ang-2 release from Weibel–Palade bodies (WPBs) being regulated by endothelial nitric oxide (NO). We explored the relationships between endothelial NO bioavailability, Ang-2, VEGF, tissue perfusion, and clinical outcomes in SM. We measured plasma Ang-2 and VEGF, together with biomarkers of severity from 146 adults with and without SM, in parallel with longitudinal measures of endothelial function by using reactive hyperemia peripheral arterial tonometry (a measure of endothelial NO bioavailability). Regression was used to relate concentrations of Ang-2/VEGF with malaria disease severity, biomarkers of perfusion, endothelial activation, and parasite biomass. The longitudinal relationship between Ang-2 and endothelial function was assessed by using a mixed-effects model. Ang-2 concentrations were elevated in SM and associated with increased venous lactate, plasma intercellular cell adhesion molecule-1 concentrations, parasite biomass, and mortality. In contrast, VEGF concentrations were inversely associated with these biomarkers. Ang-2 concentrations were significantly better predictors of death than venous lactate (P = 0.03). Recovery of endothelial function was associated with falling concentrations of Ang-2. Ang-2 release from endothelial cells with reduced NO bioavailability is likely to contribute to endothelial activation, sequestered parasite biomass, impaired perfusion, and poor outcome in severe falciparum malaria. Agents that improve endothelial NO, reduce WPB exocytosis, and/or antagonize Ang-2 may have therapeutic roles in SM.
DOI http://dx.doi.org/10.1073/pnas.0805782105   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
 
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Created: Thu, 07 May 2009, 08:47:07 CST by Sarena Wegener