Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells
<p dir="ltr"><u>Raynaud's phenomenon</u> (RP) is a vascular disease characterized by exaggerated <u>vasoconstriction</u> in response to stressors, mainly cold and emotional stress. This<u> vasoconstriction</u> is mediated solely by alpha 2C-ad...
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| مؤلفون آخرون: | , , , |
| منشور في: |
2025
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| _version_ | 1864513538507145216 |
|---|---|
| author | Manal M. Fardoun (22303813) |
| author2 | Ayah Matar (22303816) Maha Khachab (21633485) Ali H. Dakroub (22303819) Ali H. Eid (5461829) |
| author2_role | author author author author |
| author_facet | Manal M. Fardoun (22303813) Ayah Matar (22303816) Maha Khachab (21633485) Ali H. Dakroub (22303819) Ali H. Eid (5461829) |
| author_role | author |
| dc.creator.none.fl_str_mv | Manal M. Fardoun (22303813) Ayah Matar (22303816) Maha Khachab (21633485) Ali H. Dakroub (22303819) Ali H. Eid (5461829) |
| dc.date.none.fl_str_mv | 2025-05-21T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.pcad.2025.01.002 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Cigarette_smoke_extract_induces_p38-mediated_expression_and_ROS_rho-mediated_translocation_of_alpha_2C_adrenoceptor_in_human_microvascular_smooth_muscle_cells/30198232 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Cardiovascular medicine and haematology Pharmacology and pharmaceutical sciences Health sciences Public health Cigarette smoke extract Reactive oxygen species α2C-adrenoceptor Raynaud's phenomenon |
| dc.title.none.fl_str_mv | Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr"><u>Raynaud's phenomenon</u> (RP) is a vascular disease characterized by exaggerated <u>vasoconstriction</u> in response to stressors, mainly cold and emotional stress. This<u> vasoconstriction</u> is mediated solely by alpha 2C-adrenoceptors (α<sub>2</sub><sub>C</sub>-AR) expressed in <u>vascular smooth muscle cells </u>of dermal <u>arterioles</u>. Several factors, among which is cigarette smoking, are associated with aggravated symptoms of and increased risk for RP. Evidence shows that cigarette smoking induces the production of <u>reactive oxygen species</u> (ROS), which is a major driver of RP pathogenesis. However, the exact mechanism by which smoking contributes to RP or α<sub>2</sub><sub>C</sub>-AR remains unclear. Here, we show that cigarette smoke extract (CSE) upregulates the expression of α<sub>2</sub><sub>C</sub>-AR in a concentration- and time-dependent manner in VSMCs extracted from human dermal arterioles. This increase is associated with the activation of <u>p38 MAPK</u>, as pretreatment with SB-202190, a p38 specific inhibitor, attenuated CSE-induced α<sub>2</sub><sub>C</sub>-AR expression. Furthermore, our results show that CSE induces ROS production followed by increased RhoA activation. We also show that CSE induces translocation of vascular α<sub>2</sub><sub>C</sub>-AR to the plasma membrane, and that this mobilization is attenuated by inhibiting ROS via <i>N</i>-acetylcysteine or <u>apocynin</u>. Similarly, inhibition of <u>Rho kinase</u> via H- 11522 abolished CSE-induced α<sub>2</sub><sub>C</sub>-AR translocation. Collectively, these results indicate that CSE activates two different <u>signaling pathways</u> to induce the expression and the translocation of α<sub>2</sub><sub>C</sub>-AR. While CSE activates a p38-dependent mechanism to increase α<sub>2</sub><sub>C</sub>AR expression, it initiates the receptor's spatial and functional <u>rescue</u> via a ROS/RhoA signaling pathway. These results provide mechanistic insight into the effect of cigarette smoking on RP, and further reinforce that smoking avoidance/cessation is critical to manage this disease, especially in the <u>absence</u> of a definitive drug for RP.</p><h2>Other Information</h2><p dir="ltr">Published in: Progress in Cardiovascular Diseases<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.pcad.2025.01.002" target="_blank">https://dx.doi.org/10.1016/j.pcad.2025.01.002</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_065c2d70f187ab33a4f1cd5479ed071f |
| identifier_str_mv | 10.1016/j.pcad.2025.01.002 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/30198232 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cellsManal M. Fardoun (22303813)Ayah Matar (22303816)Maha Khachab (21633485)Ali H. Dakroub (22303819)Ali H. Eid (5461829)Biomedical and clinical sciencesCardiovascular medicine and haematologyPharmacology and pharmaceutical sciencesHealth sciencesPublic healthCigarette smoke extractReactive oxygen speciesα2C-adrenoceptorRaynaud's phenomenon<p dir="ltr"><u>Raynaud's phenomenon</u> (RP) is a vascular disease characterized by exaggerated <u>vasoconstriction</u> in response to stressors, mainly cold and emotional stress. This<u> vasoconstriction</u> is mediated solely by alpha 2C-adrenoceptors (α<sub>2</sub><sub>C</sub>-AR) expressed in <u>vascular smooth muscle cells </u>of dermal <u>arterioles</u>. Several factors, among which is cigarette smoking, are associated with aggravated symptoms of and increased risk for RP. Evidence shows that cigarette smoking induces the production of <u>reactive oxygen species</u> (ROS), which is a major driver of RP pathogenesis. However, the exact mechanism by which smoking contributes to RP or α<sub>2</sub><sub>C</sub>-AR remains unclear. Here, we show that cigarette smoke extract (CSE) upregulates the expression of α<sub>2</sub><sub>C</sub>-AR in a concentration- and time-dependent manner in VSMCs extracted from human dermal arterioles. This increase is associated with the activation of <u>p38 MAPK</u>, as pretreatment with SB-202190, a p38 specific inhibitor, attenuated CSE-induced α<sub>2</sub><sub>C</sub>-AR expression. Furthermore, our results show that CSE induces ROS production followed by increased RhoA activation. We also show that CSE induces translocation of vascular α<sub>2</sub><sub>C</sub>-AR to the plasma membrane, and that this mobilization is attenuated by inhibiting ROS via <i>N</i>-acetylcysteine or <u>apocynin</u>. Similarly, inhibition of <u>Rho kinase</u> via H- 11522 abolished CSE-induced α<sub>2</sub><sub>C</sub>-AR translocation. Collectively, these results indicate that CSE activates two different <u>signaling pathways</u> to induce the expression and the translocation of α<sub>2</sub><sub>C</sub>-AR. While CSE activates a p38-dependent mechanism to increase α<sub>2</sub><sub>C</sub>AR expression, it initiates the receptor's spatial and functional <u>rescue</u> via a ROS/RhoA signaling pathway. These results provide mechanistic insight into the effect of cigarette smoking on RP, and further reinforce that smoking avoidance/cessation is critical to manage this disease, especially in the <u>absence</u> of a definitive drug for RP.</p><h2>Other Information</h2><p dir="ltr">Published in: Progress in Cardiovascular Diseases<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.pcad.2025.01.002" target="_blank">https://dx.doi.org/10.1016/j.pcad.2025.01.002</a></p>2025-05-21T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.pcad.2025.01.002https://figshare.com/articles/journal_contribution/Cigarette_smoke_extract_induces_p38-mediated_expression_and_ROS_rho-mediated_translocation_of_alpha_2C_adrenoceptor_in_human_microvascular_smooth_muscle_cells/30198232CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/301982322025-05-21T09:00:00Z |
| spellingShingle | Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells Manal M. Fardoun (22303813) Biomedical and clinical sciences Cardiovascular medicine and haematology Pharmacology and pharmaceutical sciences Health sciences Public health Cigarette smoke extract Reactive oxygen species α2C-adrenoceptor Raynaud's phenomenon |
| status_str | publishedVersion |
| title | Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells |
| title_full | Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells |
| title_fullStr | Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells |
| title_full_unstemmed | Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells |
| title_short | Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells |
| title_sort | Cigarette smoke extract induces p38-mediated expression and ROS/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells |
| topic | Biomedical and clinical sciences Cardiovascular medicine and haematology Pharmacology and pharmaceutical sciences Health sciences Public health Cigarette smoke extract Reactive oxygen species α2C-adrenoceptor Raynaud's phenomenon |