Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke

Gili Kenet, Jane Freedman, Boris Shenkman, Eskaraev Regina, Frida Brok-Simoni, Fanny Holzman, Fotini Vavva, Nathan Brand, Alan Michelson, Maria Trolliet, Joseph Loscalzo, Aida Inbal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

In a previous report by Freedman et al (J Clin Invest. 1996;97:979- 987), plasma from 2 brothers with stroke or transient ischemic attack inactivated the antiplatelet effects of nitric oxide (NO), and this effect was found to be a consequence of a deficiency of plasma glutathione peroxidase (GSH-Px). In this study, we attempted to define the generalizability of this deficiency by studying NO-mediated antiplatelet effects in 7 families with familial childhood stroke. Seven families with familial childhood stroke that consecutively presented to a large referral center were included in the study. We monitored ADP-induced aggregation of normal gel-filtered platelets (GFP) in platelet-poor plasma (PPP) from normal individuals and from patients in the presence or absence of an NO donor (S- nitrosoglutathione). Surface P-selectin expression of normal GFP in patients' PPP was analyzed by flow cytometry after incubation with a P-selectin- specific monoclonal antibody in the presence or absence of the NO donor. We also measured GSH-Px activity in plasmas from family members and normal controls using standard methods. In 6 of 7 families, NO failed to inhibit platelet P-selectin expression and platelet aggregation in PPP from the affected family members and some of their relatives. Of 4 families studied, 3 probands and their corresponding affected parent had 50% decrease in plasma GSH-Px activity. In some patients with childhood stroke, impaired metabolism of reactive oxygen species as a result of reduced GSH-Px activity results in NO insufficiency that affects normal platelet inhibitory mechanisms and predisposes to arterial thrombosis.

Original languageEnglish
Pages (from-to)2017-2023
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume19
Issue number8
DOIs
StatePublished - Aug 1999

Funding

FundersFunder number
National Heart, Lung, and Blood InstituteR01HL053993

    Keywords

    • Glutathione peroxidase
    • Nitric oxide
    • Platelets
    • Stroke

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