Selective inhibition of Panx1 channels decreases hemostasis and thrombosis in vivo
| Autor: | Graziano Pelli, Beat A. Imhof, Filippo Molica, Sandrine Morel, Brenda R. Kwak, Aurélie Hautefort, Pierre Fontana, Merlijn J. Meens, Yalin Emre, Eliana Scemes |
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| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Nerve Tissue Proteins ddc:616.07 030204 cardiovascular system & hematology Connexins 03 medical and health sciences Mice 0302 clinical medicine Bleeding time In vivo Internal medicine Blocking antibody medicine Animals Humans Platelet Mesenteric arteries ddc:616 Hemostasis medicine.diagnostic_test business.industry Thrombosis Hematology medicine.disease 3. Good health medicine.anatomical_structure Endocrinology 030220 oncology & carcinogenesis medicine.symptom business Vasoconstriction |
| Zdroj: | Thrombosis Research, Vol. 183 (2019) pp. 56-62 |
| ISSN: | 1879-2472 0049-3848 |
| Popis: | Background Hemostasis is a tightly regulated physiological process to rapidly induce hemostatic plugs at sites of vascular injury. Inappropriate activation of this process may lead to thrombosis, i.e. pathological blood clot formation in uninjured vessels or on atherosclerotic lesions. ATP release through Pannexin1 (Panx1) membrane channels contributes to collagen-induced platelet aggregation in vitro. Objective To investigate the effects of genetic and pharmacological inhibition of Panx1 on hemostasis and thrombosis in vivo. Results Bleeding time after tail clipping was increased by 2.5-fold in Panx1−/− mice compared to wild-type controls, suggesting that Panx1 deficiency impairs primary hemostasis. Wire myography on mesenteric arteries revealed diminished vasoconstriction in response to phenylephrine or U446619 in Panx1−/− mice. Mice with platelet-specific deletion of Panx1 (Panx1PDel) displayed 2-fold longer tail bleeding times than Panx1fl/fl controls. Moreover, venous thromboembolism (VTE) after injection of collagen/epinephrine in the jugular vein was reduced in Panx1−/− and Panx1PDel mice. Panx1PDel mice also showed reduced FeCl3-induced thrombosis in mesenteric arteries. BrilliantBlue-FCF, a Panx1 channel inhibitor, decreased collagen-induced platelet aggregation in vitro, increased tail bleeding time and reduced VTE in wild-type mice. Furthermore, we developed a specific Panx1 blocking antibody targeting a Panx1 extracellular loop, which reduced ATP release from platelets in vitro. Treating wild-type mice with this antibody increased tail bleeding time and decreased VTE compared to control antibody. Conclusions Panx1 channel deletion or inhibition diminishes clot formation during hemostasis and thrombosis in vivo. Blocking Panx1 channels may be an attractive strategy for modulating platelet aggregation in thrombotic disease. |
| Databáze: | OpenAIRE |
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