Effects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on PAR-1/PAR-3 cleavage
Abstract Patients with obstructive sleep apnea/hypopnea (OSA) are at high risk of cerebrovascular diseases leading to cognitive impairment. The oxidative stress generated by intermittent hypoxia (IH) could lead to an increase in blood–brain barrier (BBB) permeability, an essential interface for the...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-15592-x |
| _version_ | 1818192807448281088 |
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| author | Cindy Zolotoff Clémentine Puech Frédéric Roche Nathalie Perek |
| author_facet | Cindy Zolotoff Clémentine Puech Frédéric Roche Nathalie Perek |
| author_sort | Cindy Zolotoff |
| collection | DOAJ |
| description | Abstract Patients with obstructive sleep apnea/hypopnea (OSA) are at high risk of cerebrovascular diseases leading to cognitive impairment. The oxidative stress generated by intermittent hypoxia (IH) could lead to an increase in blood–brain barrier (BBB) permeability, an essential interface for the protection of the brain. Moreover, in patients with OSA, blood coagulation could be increased leading to cardiovascular complications. Thrombin is a factor found increased in these populations that exerts various cellular effects through activation of protease activated receptors (PARs). Thus, we have evaluated in an in vitro BBB model the association of IH with thrombin at two concentrations. We measured the apparent BBB permeability, expression of tight junctions, ROS production, HIF-1α expression, and cleavage of PAR-1/PAR-3. Pre-treatment with dabigatran was performed. IH and higher thrombin concentrations altered BBB permeability: high levels of HIF-1α expression, ROS and PAR-1 activation compared to PAR-3 in such conditions. Conversely, lower concentration of thrombin associated with IH appear to have a protective effect on BBB with a significant cleavage of PAR-3. Dabigatran reversed the deleterious effect of thrombin at high concentrations but also suppressed the beneficial effect of low dose thrombin. Therefore, thrombin and PARs represent novel attractive targets to prevent BBB opening in OSA. |
| first_indexed | 2024-12-12T00:36:22Z |
| format | Article |
| id | doaj.art-301a8ca8db584126934da7ab4f2e281c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-12T00:36:22Z |
| publishDate | 2022-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-301a8ca8db584126934da7ab4f2e281c2022-12-22T00:44:21ZengNature PortfolioScientific Reports2045-23222022-07-0112111410.1038/s41598-022-15592-xEffects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on PAR-1/PAR-3 cleavageCindy Zolotoff0Clémentine Puech1Frédéric Roche2Nathalie Perek3INSERM, U1059, Sainbiose, Dysfonction Vasculaire et Hémostase, Université Jean Monnet Saint-EtienneINSERM, U1059, Sainbiose, Dysfonction Vasculaire et Hémostase, Université Jean Monnet Saint-EtienneINSERM, U1059, Sainbiose, Dysfonction Vasculaire et Hémostase, Université Jean Monnet Saint-EtienneINSERM, U1059, Sainbiose, Dysfonction Vasculaire et Hémostase, Université Jean Monnet Saint-EtienneAbstract Patients with obstructive sleep apnea/hypopnea (OSA) are at high risk of cerebrovascular diseases leading to cognitive impairment. The oxidative stress generated by intermittent hypoxia (IH) could lead to an increase in blood–brain barrier (BBB) permeability, an essential interface for the protection of the brain. Moreover, in patients with OSA, blood coagulation could be increased leading to cardiovascular complications. Thrombin is a factor found increased in these populations that exerts various cellular effects through activation of protease activated receptors (PARs). Thus, we have evaluated in an in vitro BBB model the association of IH with thrombin at two concentrations. We measured the apparent BBB permeability, expression of tight junctions, ROS production, HIF-1α expression, and cleavage of PAR-1/PAR-3. Pre-treatment with dabigatran was performed. IH and higher thrombin concentrations altered BBB permeability: high levels of HIF-1α expression, ROS and PAR-1 activation compared to PAR-3 in such conditions. Conversely, lower concentration of thrombin associated with IH appear to have a protective effect on BBB with a significant cleavage of PAR-3. Dabigatran reversed the deleterious effect of thrombin at high concentrations but also suppressed the beneficial effect of low dose thrombin. Therefore, thrombin and PARs represent novel attractive targets to prevent BBB opening in OSA.https://doi.org/10.1038/s41598-022-15592-x |
| spellingShingle | Cindy Zolotoff Clémentine Puech Frédéric Roche Nathalie Perek Effects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on PAR-1/PAR-3 cleavage Scientific Reports |
| title | Effects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on PAR-1/PAR-3 cleavage |
| title_full | Effects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on PAR-1/PAR-3 cleavage |
| title_fullStr | Effects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on PAR-1/PAR-3 cleavage |
| title_full_unstemmed | Effects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on PAR-1/PAR-3 cleavage |
| title_short | Effects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on PAR-1/PAR-3 cleavage |
| title_sort | effects of intermittent hypoxia with thrombin in an in vitro model of human brain endothelial cells and their impact on par 1 par 3 cleavage |
| url | https://doi.org/10.1038/s41598-022-15592-x |
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