Effect of ionizing radiation on cellular procoagulability and co-ordinated gene alterations

Goldin-Lang, Petra; Pels, Klaus; Tran, Quoc-Viet; Szotowski, Bjoern; Wittchen, Frank; Antoniak, Silvio; Willich, Tobias; Witt, Henning; Hummel, Michael; Lenze, Dido; Poller, Wolfgang; Schultheiss, Heinz‐Peter; Rauch, Ursula

doi:10.3324/haematol.10702

Cited by 14 publications

(5 citation statements)

References 36 publications

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“…We demonstrated the regulatory level of the PI3K/Akt pathway to be distinct from the transcriptional regulation level of NFκB. [30][31][32][33] Inhibition of the PI3K/Akt pathway by the pharmacologic inhibitor, LY294002, reduced the TNF-α-induced mRNA expression of asHTF, but not flTF, in a time-and concentration-dependent manner. In contrast, the inhibition of the transcription factor NFκB diminished the expression of both TF isoforms post stimulation with the pro-inflammatory cytokine TNF-α.…”

Section: Discussionmentioning

confidence: 97%

Role of the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway in Regulating Alternative Splicing of Tissue Factor mRNA in Human Endothelial Cells

Eisenreich

Malz

Pepke

et al. 2009

Circ J

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Background: Tissue factor (TF) is the primary initiator of blood coagulation. In response to tumor necrosis factor (TNF)-α human umbilical vein endothelial cells (HUVECs) express 2 TF isoforms: a soluble alternatively spliced isoform (asHTF) and membrane-bound "full length" (fl)TF. How the differential TF isoform expression is regulated is still unknown. This study compared the impact of PI3K/Akt pathway inhibition on alternative splicing of TF in HUVECs, to the influence of transcriptional regulation by inhibiting nuclear factor κ B (NFκB). Methods and Results:The mRNA expression of TF isoforms was assessed by real-time PCR, the thrombogenic activity was measured by a chromogenic TF activity assay and the phosphorylation state of serine/arginine-rich (SR) proteins was analyzed by western blotting. Transfection of HUVECs was done 72 h before the inhibition experiments were performed. PI3K/Akt pathway inhibition reduced the mRNA expression of asHTF but not flTF. Inhibition of NFκB reduced the expression of both isoforms. Moreover, the PI3K/Akt pathway inhibition, but not that of NFκB, modified the phosphorylation of the SR proteins SRp75, SRp55 and SF2/ASF. Additionally, overexpression of SF2/ASF and SRp75 influenced the differential TF-isoform expression in HUVECs. Conclusions: The PI3K/Akt pathway modulates alternative splicing of TF in HUVECs, distinct from transcriptional regulation. (Circ J 2009; 73: 1746 -1752

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Section: Discussionmentioning

confidence: 97%

Role of the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway in Regulating Alternative Splicing of Tissue Factor mRNA in Human Endothelial Cells

Eisenreich

Malz

Pepke

et al. 2009

Circ J

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“…55 In addition, ionizing radiation, which induces significant TYMP expression, has been associated with thrombotic vascular occlusion. 56 In the current study, we found that TYMP deficiency or inhibition does not affect platelet binding to the collagen-coated surface; however, it dramatically attenuated platelet aggregation on the collagencoated surface in a flow chamber assay. In combination with our published data, 22 these data further demonstrated that TYMP likely plays a more important role in the GPVI signaling pathway.…”

mentioning

confidence: 38%

Targeting Thymidine Phosphorylase with Tipiracil Hydrochloride is a Safe and Effective Antithrombotic Therapy

Zulfiker

Belcher

et al. 2020

Preprint

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Rationale:Most of the current anti-platelet drugs inhibit platelet function permanently and have systemic side effects, including thrombocytopenia and hemorrhage. We previously found that thymidine phosphorylase (TYMP), a platelet cytoplasmic protein, facilitates multiple agonist induced platelet activation and enhances thrombosis. A specific TYMP inhibitor, namely, tipiracil hydrochloride (TPI), has been approved by the U.S. Food and Drug Administration for clinical use as an auxiliary drug making it possible to be repositioned as an anti-platelet medicine. Objective:We aimed to test the hypothesis that TPI is a novel and safe anti-platelet drug by examining its role in platelet activation and thrombosis using both in vitro and in vivo studies. Methods and Results:By co-expression of TYMP and Lyn or Lyn-SH3 domain tagged with glutathione S-transferase, we showed the direct evidence that TYMP binds to the SH3 domain in its partners. TYMP haplodeficiency is sufficient to inhibit thrombosis in vivo regardless of gender. TPI treatment rapidly inhibited collagen-and ADP-induced platelet aggregation, which copied the phenotype of TYMP deficient platelets. Under both normal and hyperlipidemic conditions, treating wild type (WT) mice with TPI via intraperitoneal injection, intravenous injection, or gavage feeding dramatically inhibited thrombosis without inducing significant bleeding. Even administered above the effective dose, TPI has a lower bleeding side effect compared to aspirin and clopidogrel. Most importantly, intravenously delivery of TPI alone or combined with tissue plasminogen activator dramatically inhibited the growth of developing thrombi. Dual administration of very low dose of aspirin and TPI also dramatically inhibited thrombosis without disturbing hemostasis. Conclusion:This pharmacological study demonstrated that TYMP participates in multiple signaling pathways in platelet and plays a mechanistic role in regulating platelet activation and thrombosis. TPI, a specific TYMP inhibitor, would be a novel safe anti-platelet and anti-thrombosis medicine. Cellix flow chamber-based platelet adhesion and aggregation assayCellix flow chambers were coated with collagen 10 μg/mL in PBS. Whole blood was drawn from mouse inferior vena cava using 0.109 M sodium citrate as an anticoagulant, stained with Rhodamine 6G, and then used for the flow chamber mediated adhesion and aggregation assay. Some of the whole blood was treated with or without TPI before it was perfused into the chamber.Compare the therapeutic effect of TPI to aspirin and clopidogrel 5 8 to 10 week-old male WT mice were gavage fed with either TPI, aspirin, or clopidogrel once daily for one week, then subsequently used in an in vivo thrombosis study. Tail bleeding assay was conducted on these mice immediately after the thrombosis study. Examine the effect of TYMP inhibition on thrombosis under hyperlipidemiaWT mice were fed a western diet (WD, TD.88137) for a total of 4 weeks. For a separate group of mice, the diet was changed to a customized diet (TD.1...

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“…Furthermore these MVs could be implicated in a cross-talk communication to promote the initiation and the expansion of the coagulation process 43 , 44 . EMVs and MMVs are known to be procoagulant due to the presence of TF and phosphatidylserine at their surface 45 , 46 . More specifically, several studies suggested that MMVs could constitute the most important source of circulating TF and are able to transfer their TF to the activated platelets to propagate the coagulation process 43 , 47 .…”

Section: Discussionmentioning

confidence: 99%

Circulating microvesicles correlate with radiation proctitis complication after radiotherapy

Ribault

Benadjaoud

Squiban

et al. 2023

Sci Rep

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In a large retrospective study, we assessed the putative use of circulating microvesicles (MVs), as innovative biomarkers of radiation toxicity in a cohort of 208 patients with prostate adenocarcinoma overexposed to radiation. The level of platelet (P)-, monocyte (M)- and endothelial (E)-derived MVs were assessed by flow cytometry. Rectal bleeding toxicity scores were collected at the time of blood sampling and during the routine follow-up and were tested for association with MVs using a multivariate logistic regression. MVs dosimetric correlation was investigated using dose volume histograms information available for a subset of 36 patients. The number of PMVs was significantly increased in patients with highest toxicity grades compared to lower grades. Risk prediction analysis revealed that increased numbers of PMVs, and an increased amount of MMVs relative to EMVs, were associated with worst rectal bleeding grade compared to the time of blood sampling. Moreover, a significant correlation was found between PMV and MMV numbers, with the range of doses up to the median exposure (40 Gy) of bladder/rectum and anterior rectal wall, respectively. MVs could be considered as new biomarkers to improve the identification of patients with high toxicity grade and may be instrumental for the prognosis of radiation therapy complications.

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Effect of ionizing radiation on cellular procoagulability and co-ordinated gene alterations

Cited by 14 publications

References 36 publications

Role of the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway in Regulating Alternative Splicing of Tissue Factor mRNA in Human Endothelial Cells

Role of the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway in Regulating Alternative Splicing of Tissue Factor mRNA in Human Endothelial Cells

Targeting Thymidine Phosphorylase with Tipiracil Hydrochloride is a Safe and Effective Antithrombotic Therapy

Circulating microvesicles correlate with radiation proctitis complication after radiotherapy

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