Fardoun Manal M, Matar Ayah, Khachab Maha, Dakroub Ali H, Eid Ali H
Faculty of Medicine, American University of Beirut, Beirut, P.O. Box 11-0236, Lebanon.
Mayo Clinic, MN, Rochester, USA.
Prog Cardiovasc Dis. 2025 Mar-Apr;89:119-126. doi: 10.1016/j.pcad.2025.01.002. Epub 2025 Jan 9.
Raynaud's phenomenon (RP) is a vascular disease characterized by exaggerated vasoconstriction in response to stressors, mainly cold and emotional stress. This vasoconstriction is mediated solely by alpha 2C-adrenoceptors (α-AR) expressed in vascular smooth muscle cells of dermal arterioles. 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 reactive oxygen species (ROS), which is a major driver of RP pathogenesis. However, the exact mechanism by which smoking contributes to RP or α-AR remains unclear. Here, we show that cigarette smoke extract (CSE) upregulates the expression of α-AR in a concentration- and time-dependent manner in VSMCs extracted from human dermal arterioles. This increase is associated with the activation of p38 MAPK, as pretreatment with SB-202190, a p38 specific inhibitor, attenuated CSE-induced α-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-AR to the plasma membrane, and that this mobilization is attenuated by inhibiting ROS via N-acetylcysteine or apocynin. Similarly, inhibition of Rho kinase via H- 11522 abolished CSE-induced α-AR translocation. Collectively, these results indicate that CSE activates two different signaling pathways to induce the expression and the translocation of α-AR. While CSE activates a p38-dependent mechanism to increase α-AR expression, it initiates the receptor's spatial and functional rescue 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 absence of a definitive drug for RP.
雷诺现象（RP）是一种血管疾病，其特征是在应激源（主要是寒冷和情绪应激）作用下血管过度收缩。这种血管收缩仅由真皮小动脉血管平滑肌细胞中表达的α2C肾上腺素能受体（α-AR）介导。包括吸烟在内的多种因素与RP症状加重和风险增加有关。有证据表明，吸烟会诱导活性氧（ROS）的产生，这是RP发病机制的主要驱动因素。然而，吸烟导致RP或α-AR的确切机制尚不清楚。在此，我们表明香烟烟雾提取物（CSE）在从人真皮小动脉提取的血管平滑肌细胞（VSMCs）中以浓度和时间依赖性方式上调α-AR的表达。这种增加与p38丝裂原活化蛋白激酶（MAPK）的激活有关，因为用p38特异性抑制剂SB-202190预处理可减弱CSE诱导的α-AR表达。此外，我们的结果表明CSE诱导ROS产生，随后RhoA激活增加。我们还表明CSE诱导血管α-AR向质膜转位，并且通过N-乙酰半胱氨酸或阿朴吗啡抑制ROS可减弱这种转位。同样，通过H-11522抑制Rho激酶可消除CSE诱导的α-AR转位。总体而言，这些结果表明CSE激活两种不同的信号通路来诱导α-AR的表达和转位。虽然CSE激活p38依赖性机制以增加α-AR表达，但它通过ROS/RhoA信号通路启动受体的空间和功能拯救。这些结果为吸烟对RP的影响提供了机制性见解，并进一步强化了避免/戒烟对于管理这种疾病至关重要，特别是在缺乏针对RP的明确药物的情况下。
