Differential impact of prostaglandin H synthase 1 knockdown on platelets and parturition
| Autor: | Andres J. Klein-Szanto, Ying Yu, Yan Cheng, Colin D. Funk, Jinjin Fan, Xin-Sheng Chen, Garret A. FitzGerald |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Blood Platelets
Male medicine.medical_specialty Thromboxane Biology Article Preeclampsia Thromboxane A2 chemistry.chemical_compound Mice Pre-Eclampsia Pregnancy Internal medicine Luteolysis medicine Animals Edema Humans Platelet Platelet activation Receptor Progesterone Mice Knockout Arachidonic Acid Aspirin Estradiol Ovary Uterus Parturition Membrane Proteins General Medicine medicine.disease Oxytocin receptor Mice Inbred C57BL Endocrinology chemistry Prostaglandin-Endoperoxide Synthases Receptors Oxytocin Cyclooxygenase 1 Female |
| Popis: | Platelet activation is a hallmark of severe preeclampsia, and platelet PGH synthase 1-derived (PGHS1-derived) thromboxane A(2) (TxA(2)) has been implicated in its pathogenesis. However, genetic disruption of PGHS1 delays parturition. We created hypomorphic PGHS1 (PGHS1(Neo/Neo)) mice, in which the substantial but tissue-dependent variability in the inhibition of PGHS1-derived eicosanoids achieved by low-dose aspirin treatment is mimicked, to assess the relative impact of this strategy on hemostatic and reproductive function. Depression of platelet TxA(2) by 98% in PGHS1(Neo/Neo) mice decreased platelet aggregation and prevented thrombosis. Similarly, depression of macrophage PGE(2) by 75% was associated with selectively impaired inflammatory responses. PGF(2alpha) at 8% WT levels was sufficient to induce coordinated temporal oxytocin receptor (OTR) expression in uterus and normal ovarian luteolysis in PGHS1(Neo/Neo) mice at late gestation, while absence of PGHS1 expression in null mice delayed OTR induction and the programmed decrease of serum progesterone during parturition. Thus, extensive but tissue-dependent variability in PG suppression, as occurs with low-dose aspirin treatment, prevents thrombosis and impairs the inflammatory response but sustains parturition. PGHS1(Neo/Neo) mice provide a model of low-dose aspirin therapy that elucidates how prevention or delay of preeclampsia might be achieved without compromising reproductive function. |
| Databáze: | OpenAIRE |
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