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17β‐OESTRADIOL PARTIALLY ATTENUATES THE INHIBITION OF NITRIC OXIDE SYNTHASE‐3 BY ADVANCED GLYCATION END‐PRODUCTS IN HUMAN PLATELETS
Author(s) -
Chen Lu,
Liu Yuan,
Cui Bota,
Mi Qiongyu,
Huang Yan,
Fan Leming,
Chen Qi,
Tang James,
Ferro Albert,
Ji Yong
Publication year - 2007
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2007.04680.x
Subject(s) - glycation , medicine , endocrinology , chemistry , phosphoserine , albumin , nitric oxide , nitric oxide synthase , platelet , serine , diabetes mellitus , phosphorylation , biochemistry , biology
SUMMARY1 Diabetes mellitus predisposes to and female sex protects against arterial thrombosis. The aim of the present study was to determine whether advanced glycation end‐products (AGE), which accumulate in diabetes, impair platelet function through effects on platelet nitric oxide (NO) generation and whether this can be prevented by 17β‐oestradiol. 2 Aggregation responses of human platelet‐rich plasma to ADP were determined in the absence or presence of 200 mg/L AGE‐modified albumin (AGE‐albumin), 10 −5 mol/L 17β‐oestradiol and 10 −5 mol/L ICI 182 780 (the pure oestrogen receptor antagonist). 3 Intraplatelet cGMP, an index of bioactive NO, was measured by radioimmunoassay and expression of nitric oxide synthase (NOS)‐3, phosphoserine‐1177‐NOS‐3 and O ‐glycosylated NOS‐3 was quantified by western blotting in response to these same treatments. 4 Advanced glycation end‐products–albumin increased platelet aggregatory responses to ADP. This increase was largely prevented by 17β‐oestradiol. Advanced glycation end‐products–albumin decreased and 17β‐oestradiol increased intraplatelet NO‐attributable cGMP and 17β‐oestradiol attenuated the AGE‐albumin‐induced decrease in NO‐attributable cGMP. Despite no effect on NOS‐3 expression, AGE‐albumin decreased and 17β‐oestradiol increased phosphoserine‐1177‐NOS‐3 and 17β‐oestradiol largely prevented the decrease in phosphoserine‐1177‐NOS‐3 induced by AGE‐albumin. Alone, AGE‐albumin increased O ‐glycosylation of NOS‐3 by N ‐acetylglucosamine, an effect largely inhibited by 17β‐oestradiol. 5 In conclusion, AGE‐albumin inhibits platelet NO biosynthesis through effects on serine phosphorylation and O‐ glycosylation of platelet NOS‐3 and this may explain, at least in part, the increase in platelet aggregability induced by AGE‐albumin. These effects of AGE‐albumin are largely prevented by 17β‐oestradiol. These actions may contribute to the effects of diabetes and sex on arterial thrombosis in vivo .