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

Tsin Yeo, D LAMPAH, Retno Gitawati, Emiliana Tjitra, Enny Kenangalem, Kim Piera, Ric Price, Stephen Duffull, David S Celermajer, Nicholas Anstey

    Research output: Contribution to journalArticleResearchpeer-review

    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 SMand 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. � 2008 by The National Academy of Sciences of the USA.
    Original languageEnglish
    Pages (from-to)17097-17102
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume105
    Issue number44
    Publication statusPublished - 2008

    Fingerprint

    Angiopoietin-2
    Falciparum Malaria
    Nitric Oxide
    Vascular Endothelial Growth Factor A
    Malaria
    Weibel-Palade Bodies
    Biomass
    Biological Availability
    Parasites
    Perfusion
    Biomarkers
    Lactic Acid
    Angiogenesis Inducing Agents
    Recovery of Function
    Hyperemia
    Manometry
    Exocytosis
    Cell Adhesion Molecules
    Intercellular Adhesion Molecule-1
    Plasma Cells

    Cite this

    Yeo, Tsin ; LAMPAH, D ; Gitawati, Retno ; Tjitra, Emiliana ; Kenangalem, Enny ; Piera, Kim ; Price, Ric ; Duffull, Stephen ; Celermajer, David S ; Anstey, Nicholas. / Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 44. pp. 17097-17102.
    @article{90ae6d319a374806b2f7624efcec9e0c,
    title = "Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria",
    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 SMand 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. � 2008 by The National Academy of Sciences of the USA.",
    keywords = "angiopoietin 2, intercellular adhesion molecule 1, nitric oxide, vasculotropin, adult, article, biomass, disease severity, endothelium cell, female, human, major clinical study, malaria falciparum, male, mortality, outcome assessment, priority journal, tissue perfusion, Adolescent, Adult, Angiopoietin-2, Biological Markers, Endothelium, Vascular, Humans, Malaria, Falciparum, Middle Aged, Nitric Oxide, Prospective Studies, Severity of Illness Index, Vascular Endothelial Growth Factor A, Plasmodium falciparum",
    author = "Tsin Yeo and D LAMPAH and Retno Gitawati and Emiliana Tjitra and Enny Kenangalem and Kim Piera and Ric Price and Stephen Duffull and Celermajer, {David S} and Nicholas Anstey",
    year = "2008",
    language = "English",
    volume = "105",
    pages = "17097--17102",
    journal = "Proceedings of the National Academy of Sciences of the United States of America",
    issn = "0027-8424",
    publisher = "National Academy of Sciences (USA)",
    number = "44",

    }

    Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. / Yeo, Tsin; LAMPAH, D; Gitawati, Retno; Tjitra, Emiliana; Kenangalem, Enny; Piera, Kim; Price, Ric; Duffull, Stephen; Celermajer, David S; Anstey, Nicholas.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 44, 2008, p. 17097-17102.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria

    AU - Yeo, Tsin

    AU - LAMPAH, D

    AU - Gitawati, Retno

    AU - Tjitra, Emiliana

    AU - Kenangalem, Enny

    AU - Piera, Kim

    AU - Price, Ric

    AU - Duffull, Stephen

    AU - Celermajer, David S

    AU - Anstey, Nicholas

    PY - 2008

    Y1 - 2008

    N2 - 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 SMand 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. � 2008 by The National Academy of Sciences of the USA.

    AB - 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 SMand 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. � 2008 by The National Academy of Sciences of the USA.

    KW - angiopoietin 2

    KW - intercellular adhesion molecule 1

    KW - nitric oxide

    KW - vasculotropin

    KW - adult

    KW - article

    KW - biomass

    KW - disease severity

    KW - endothelium cell

    KW - female

    KW - human

    KW - major clinical study

    KW - malaria falciparum

    KW - male

    KW - mortality

    KW - outcome assessment

    KW - priority journal

    KW - tissue perfusion

    KW - Adolescent

    KW - Adult

    KW - Angiopoietin-2

    KW - Biological Markers

    KW - Endothelium, Vascular

    KW - Humans

    KW - Malaria, Falciparum

    KW - Middle Aged

    KW - Nitric Oxide

    KW - Prospective Studies

    KW - Severity of Illness Index

    KW - Vascular Endothelial Growth Factor A

    KW - Plasmodium falciparum

    UR - http://www.scopus.com/inward/record.url?scp=55949108502&partnerID=8YFLogxK

    M3 - Article

    VL - 105

    SP - 17097

    EP - 17102

    JO - Proceedings of the National Academy of Sciences of the United States of America

    JF - Proceedings of the National Academy of Sciences of the United States of America

    SN - 0027-8424

    IS - 44

    ER -