Low‐dose aspirin reduces hypoxia‐induced sFlt1 release via the JNK/AP‐1 pathway in human trophoblast and endothelial cells

SummaryGeneration of thromboxane A2 (TxA2) and prostacyclin (PGI2) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine skin bleeding time was investigated in 7 patients with atherosclerosis (angiographically verified obstructions of the femoral arteries) and in 7 normal control subjects apparently free of atherosclerotic lesions. Similar amounts of TxA2 (measured as thromboxane B2, TxB2) were generated at the site of plug formation in the patients with peripheral vascular disease (PVD) and in the control subjects. Significantly lower levels of PGI2 (measured as 6-keto-prostaglandin F1α, 6-keto- PGF1α) were found in blood from an injury of the microvasculature in the patients compared with the controls. These data do not suggest a major role of the platelet prostaglandin metabolism in the development of atherosclerosis. However, decreased synthesis of PGI2 by endothelial cells might contribute to the development and/or progression of atherosclerotic lesions. In the patients with PVD, low-dose aspirin (50 mg/day for 7 days) resulted in a >90% inhibition of the TxB2 production at the site of plug formation. Following low-dose aspirin 6-keto-PcF1α levels were below 20 pg/ml (limit of sensitivity of our radioimmunoassay procedure) in the majority of the samples.We therefore conclude that in patients with PVD a decreased synthesis of PGI2 by endothelial cells might contribute to the progression of atherosclerosis. Furthermore, low-dose aspirin treatment results in a similar inhibition of the platelet prostaglandin generation as recently observed in healthy subjects.

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Low dose aspirin decreases 15-hydroxyeicosatetraenoic acid (15-HETE) production by cultured human trophoblast

Journal of the Society for Gynecologic Investigation ◽

10.1016/1071-5576(95)94444-y ◽

1995 ◽

Vol 2 (2) ◽

pp. 308

Author(s):

R JOHNSON

Keyword(s):

Low Dose ◽

Hydroxyeicosatetraenoic Acid ◽

Human Trophoblast ◽

Dose Aspirin ◽

Low Dose Aspirin

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Abstract P171: Low Concentrations of Aspirin Activate Cytoprotective Signaling Pathway Genes in Human Endothelial Cells: A Gene Expression Profiling Study

Circulation Research ◽

10.1161/res.109.suppl_1.ap171 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Reena V Kartha ◽

Belinda W Cheung ◽

Subbaya Subramanian ◽

Henning Schröder

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Heme Oxygenase ◽

Low Dose ◽

Expression Profiles ◽

Fold Change ◽

Heme Oxygenase 1 ◽

Human Endothelial Cells ◽

Dose Aspirin ◽

Low Dose Aspirin

Low-dose aspirin is recommended for individuals with risk for heart disease and stroke in order to prevent thrombotic occlusive events. In addition to its well-established platelet inhibitory effects, increased expression of the antioxidant heme oxygenase-1 is considered to contribute to cardiovascular protection by aspirin. However little is known about the genome-wide changes in gene expression mediated by aspirin. In order to identify other molecular pathways and targets affected by aspirin, we investigated the global effects of aspirin treatment (3 μM and 100 μM) in vitro in human endothelial cells (Ea.hy 926) using HT-12 bead arrays (Illumina). The filtered genes were further analyzed using Ingenuity Pathway Analysis (IPA) software. We determined the gene expression profiles of endothelial cells treated with aspirin (3 μM and 100 μM) along with vehicle controls. Gene microarray analysis revealed significant upregulation of 134 genes (p <0.005 and >2 fold change) and downregulation of over 100 genes (p <0.005 and ≤0.5 fold change). Interestingly, the pattern of gene expression was similar between the two analyzed concentrations of 3 μM and 100 μM. The majority of upregulated genes were involved in gene expression, transcriptional regulation, cell-to-cell signalling and interaction and encoded transcription factors such as MAP kinases, phosphoinositide-3-kinases and cell cycle regulators (p<0.005). Several components of heterotrimeric G-proteins and G-protein-coupled receptors were also found to be upregulated which can potentially trigger phospholipase C signaling, suggesting an increase in overall intracellular second messenger signaling. In summary, our gene expression analysis suggests that aspirin at low and therapeutically relevant concentrations (3 μM) is effective in triggering cytoprotective signaling pathways some of which play a role in the regulation of heme oxygenase-1. Moreover, our study shows that low-dose aspirin results in altered expression profiles of a variety of genes. Future studies will have to address the biological and clinical relevance of these novel aspirin targets.

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Esomeprazole Lessened Ulcer Risk For Patients on Low-Dose Aspirin

Internal Medicine News ◽

10.1016/s1097-8690(06)73895-1 ◽

2006 ◽

Vol 39 (14) ◽

pp. 52

Author(s):

Doug Brunk

Keyword(s):

Low Dose ◽

Dose Aspirin ◽

Low Dose Aspirin

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Alert Issued on Low-Dose Aspirin + Ibuprofen

Clinical Psychiatry News ◽

10.1016/s0270-6644(06)71782-9 ◽

2006 ◽

Vol 34 (10) ◽

pp. 8

Author(s):

ELIZABETH MECHCATIE

Keyword(s):

Low Dose ◽

Dose Aspirin ◽

Low Dose Aspirin

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Benefits of Low-Dose Aspirin Alone Offset Costs

Family Practice News ◽

10.1016/s0300-7073(07)71179-9 ◽

2007 ◽

Vol 37 (19) ◽

pp. 11

Author(s):

KERRI WACHTER

Keyword(s):

Low Dose ◽

Dose Aspirin ◽

Low Dose Aspirin

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Investigation of the Interaction of Blood Platelets with the Coagulation System at the Site of Plug Formation In Vivo in Man - Effect of Low-Dose Aspirin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651063 ◽

1987 ◽

Vol 57 (01) ◽

pp. 062-066 ◽

Cited By ~ 36

Author(s):

P A Kyrle ◽

J Westwick ◽

M F Scully ◽

V V Kakkar ◽

G P Lewis

Keyword(s):

Platelet Activation ◽

Thrombin Generation ◽

Low Dose ◽

Bleeding Time ◽

Blood Platelets ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Plug Formation ◽

Granule Release

SummaryIn 7 healthy volunteers, formation of thrombin (represented by fibrinopeptide A (FPA) generation, α-granule release (represented by β-thromboglobulin [βTG] release) and the generation of thromboxane B2 (TxB2) were measured in vivo in blood emerging from a template bleeding time incision. At the site of plug formation, considerable platelet activation and thrombin generation were seen within the first minute, as indicated by a 110-fold, 50-fold and 30-fold increase of FPA, TxB2 and PTG over the corresponding plasma values. After a further increase of the markers in the subsequent 3 minutes, they reached a plateau during the fourth and fifth minute. A low-dose aspirin regimen (0.42 mg.kg-1.day-1 for 7 days) caused >90% inhibition of TxB2formation in both bleeding time blood and clotted blood. At the site of plug formation, a-granule release was substantially reduced within the first three minutes and thrombin generation was similarly inhibited. We conclude that (a) marked platelet activation and considerable thrombin generation occur in the early stages.of haemostasis, (b) α-granule release in vivo is partially dependent upon cyclo-oxygenase-controlled mechanisms and (c) thrombin generation at the site of plug formation is promoted by the activation of platelets.

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Increased Thromboxane Biosynthesis in Essential Thrombocythemia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649916 ◽

1995 ◽

Vol 74 (05) ◽

pp. 1225-1230 ◽

Cited By ~ 71

Author(s):

Bianca Rocca ◽

Giovanni Ciabattoni ◽

Raffaele Tartaglione ◽

Sergio Cortelazzo ◽

Tiziano Barbui ◽

...

Keyword(s):

Platelet Count ◽

Platelet Activation ◽

Essential Thrombocythemia ◽

Therapeutic Strategy ◽

Low Dose ◽

Thrombotic Risk ◽

Dose Aspirin ◽

Gender And Age ◽

Low Dose Aspirin

SummaryIn order to investigate the in vivo thromboxane (TX) biosynthesis in essential thromboeythemia (ET), we measured the urinary exeretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p <0.001) in thrombocythemic patients (4,063 ± 3,408 pg/mg creatinine; mean ± SD) than in controls (504 ± 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 >2 SD above the control mean. Patients with platelet number <1,000 × 109/1 (n = 25) had significantly higher (p <0.05) 11 -dehydro-TXB2 excretion than patients with higher platelet count (4,765 ± 3,870 pg/mg creatinine, n = 25, versus 2,279 ± 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging >55 was significantly higher than in the younger group (4,784 ± 3,948 pg/mg creatinine, n = 24, versus 2,405 ± 1,885 pg/mg creatinine, n = 16, p <0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p <0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p <0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age >55 and platelet count <1,000 × 1099/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo;2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.

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