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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| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , |
| منشور في: |
2025
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| الملخص: | <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> |
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