The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation
Background: Activation of the platelet-specific collagen receptor, glycoprotein (GP) VI, induces intracellular reactive oxygen species (ROS) production; however the relevance of ROS to GPVI-mediated platelet responses remains unclear. Objective: The objective of this study was to explore the role of...
| Main Authors: | , , , , , |
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| Format: | Journal Article |
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Elsevier BV
2014
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| Online Access: | http://hdl.handle.net/20.500.11937/7108 |
| _version_ | 1848745271275552768 |
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| author | Walsh, T. Berndt, Michael Carrim, N. Cowman, J. Kenny, D. Metharom, Pat |
| author_facet | Walsh, T. Berndt, Michael Carrim, N. Cowman, J. Kenny, D. Metharom, Pat |
| author_sort | Walsh, T. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Background: Activation of the platelet-specific collagen receptor, glycoprotein (GP) VI, induces intracellular reactive oxygen species (ROS) production; however the relevance of ROS to GPVI-mediated platelet responses remains unclear. Objective: The objective of this study was to explore the role of the ROS-producing NADPH oxidase (Nox)1 and 2 complexes in GPVI-dependent platelet activation and collagen-induced thrombus formation. Methods and results: ROS production was measured by quantitating changes in the oxidation-sensitive dye, H2DCF-DA, following platelet activation with the GPVI-specific agonist, collagen related peptide (CRP). Using a pharmacological inhibitor specific for Nox1, 2-acetylphenothiazine (ML171), and Nox2 deficient mice, we show that Nox1 is the key Nox homolog regulating GPVI-dependent ROS production. Nox1, but not Nox2, was essential for CRP-dependent thromboxane (Tx)A2 production, which was mediated in part through p38 MAPK signaling; while neither Nox1 nor Nox2 was significantly involved in regulating CRP-induced platelet aggregation/integrin αIIbβ3 activation, platelet spreading, or dense granule and α-granule release (ATP release and P-selectin surface expression, respectively). Ex-vivo perfusion analysis of mouse whole blood revealed that both Nox1 and Nox2 were involved in collagen-mediated thrombus formation at arterial shear. Conclusion: Together these results demonstrate a novel role for Nox1 in regulating GPVI-induced ROS production, which is essential for optimal p38 activation and subsequent TxA2 production, providing an explanation for reduced thrombus formation following Nox1 inhibition. |
| first_indexed | 2025-11-14T06:14:42Z |
| format | Journal Article |
| id | curtin-20.500.11937-7108 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T06:14:42Z |
| publishDate | 2014 |
| publisher | Elsevier BV |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-71082017-09-13T14:39:53Z The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation Walsh, T. Berndt, Michael Carrim, N. Cowman, J. Kenny, D. Metharom, Pat Background: Activation of the platelet-specific collagen receptor, glycoprotein (GP) VI, induces intracellular reactive oxygen species (ROS) production; however the relevance of ROS to GPVI-mediated platelet responses remains unclear. Objective: The objective of this study was to explore the role of the ROS-producing NADPH oxidase (Nox)1 and 2 complexes in GPVI-dependent platelet activation and collagen-induced thrombus formation. Methods and results: ROS production was measured by quantitating changes in the oxidation-sensitive dye, H2DCF-DA, following platelet activation with the GPVI-specific agonist, collagen related peptide (CRP). Using a pharmacological inhibitor specific for Nox1, 2-acetylphenothiazine (ML171), and Nox2 deficient mice, we show that Nox1 is the key Nox homolog regulating GPVI-dependent ROS production. Nox1, but not Nox2, was essential for CRP-dependent thromboxane (Tx)A2 production, which was mediated in part through p38 MAPK signaling; while neither Nox1 nor Nox2 was significantly involved in regulating CRP-induced platelet aggregation/integrin αIIbβ3 activation, platelet spreading, or dense granule and α-granule release (ATP release and P-selectin surface expression, respectively). Ex-vivo perfusion analysis of mouse whole blood revealed that both Nox1 and Nox2 were involved in collagen-mediated thrombus formation at arterial shear. Conclusion: Together these results demonstrate a novel role for Nox1 in regulating GPVI-induced ROS production, which is essential for optimal p38 activation and subsequent TxA2 production, providing an explanation for reduced thrombus formation following Nox1 inhibition. 2014 Journal Article http://hdl.handle.net/20.500.11937/7108 10.1016/j.redox.2013.12.023 Elsevier BV unknown |
| spellingShingle | Walsh, T. Berndt, Michael Carrim, N. Cowman, J. Kenny, D. Metharom, Pat The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation |
| title | The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation |
| title_full | The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation |
| title_fullStr | The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation |
| title_full_unstemmed | The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation |
| title_short | The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation |
| title_sort | role of nox1 and nox2 in gpvi-dependent platelet activation and thrombus formation |
| url | http://hdl.handle.net/20.500.11937/7108 |