TY - JOUR
T1 - Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke
AU - Kenet, Gili
AU - Freedman, Jane
AU - Shenkman, Boris
AU - Regina, Eskaraev
AU - Brok-Simoni, Frida
AU - Holzman, Fanny
AU - Vavva, Fotini
AU - Brand, Nathan
AU - Michelson, Alan
AU - Trolliet, Maria
AU - Loscalzo, Joseph
AU - Inbal, Aida
PY - 1999/8
Y1 - 1999/8
N2 - 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.
AB - 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.
KW - Glutathione peroxidase
KW - Nitric oxide
KW - Platelets
KW - Stroke
UR - http://www.scopus.com/inward/record.url?scp=0032810065&partnerID=8YFLogxK
U2 - 10.1161/01.ATV.19.8.2017
DO - 10.1161/01.ATV.19.8.2017
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AN - SCOPUS:0032810065
SN - 1079-5642
VL - 19
SP - 2017
EP - 2023
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 8
ER -