Wang Huazhen, Zhang Meiping, Xin Minglong, Yue Xueling, Piao Jinshun, Zhao Longguo, Bi Hehui, Wang Shiyan, Jin Chunzi, Nan Yongshan, Jin Xianglan, Cheng Xian Wu
Department of Anesthesiology, Yanbian University Hospital, Yanji, Jilin, P.R. China.
Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular Disease, Yanbian University Hospital, Yanji, Jilin, P.R. China.
FASEB J. 2025 May 15;39(9):e70546. doi: 10.1096/fj.202500724R.
Chronic psychological stress (CPS) is a significant risk factor for thrombotic cardio-cerebrovascular diseases (TCVDs). Clinical data suggest that the α-adrenergic receptor (AdR-α) agonist dexmedetomidine (Dex) can influence coagulation in stress-exposed intensive care unit patients. Given the important role of protease-activated receptor-2 (PAR-2) in vascular pathobiology, we aimed to investigate the potential effects of Dex on stress-related thrombus formation, focusing on the PAR-2 signaling pathway. Eight-week-old male mice underwent non-stress and immobilization stress with Dex treatment for 2 weeks and were then subjected to carotid artery thrombosis induction using ferric chloride (FeCl). On Day 14 post-stress, the mice exhibited increased thrombus weight and length, along with harmful alterations in the plasma levels of von Willebrand factor and metalloproteinase with thrombospondin Type 13 motifs. Additionally, arterial protein and/or mRNA levels of PAR-2, p-Akt, Bcl-2, cleaved caspase-3, cytochrome c, gp91, TNF-α, MCP-1, ICAM-1, VCAM-1, and TLR-4 were altered, accompanied by arterial endothelial loss. Dex treatment reversed these changes. Conversely, AdR-α2 blockage with yohimbine diminished the benefits of Dex. In vitro, Dex reduced stress serum-induced reactive oxygen species production and endothelial apoptosis, along with beneficial alterations in PAR-2, Bcl-2, and cytochrome c protein levels. Yohimbine diminished these effects. Thus, α-adrenergic receptor activation appeared to mitigate stress-related thrombus formation in mice undergoing FeCl-induced surgery, possibly by negatively regulating PAR-2 signaling. These findings suggest a potential therapeutic strategy for CPS-related thrombotic events in patients with TCVDs.
慢性心理应激（CPS）是血栓性心脑血管疾病（TCVDs）的一个重要危险因素。临床数据表明，α-肾上腺素能受体（AdR-α）激动剂右美托咪定（Dex）可影响处于应激状态的重症监护病房患者的凝血功能。鉴于蛋白酶激活受体-2（PAR-2）在血管病理生物学中的重要作用，我们旨在研究Dex对应激相关血栓形成的潜在影响，重点关注PAR-2信号通路。8周龄雄性小鼠接受非应激和制动应激并给予Dex治疗2周，然后使用氯化铁（FeCl）诱导颈动脉血栓形成。在应激后第14天，小鼠的血栓重量和长度增加，同时血浆血管性血友病因子水平以及含血小板反应蛋白基序的金属蛋白酶13水平出现有害变化。此外，动脉中PAR-2、p-Akt、Bcl-2、裂解的半胱天冬酶-3、细胞色素c、gp91、TNF-α、MCP-1、ICAM-1、VCAM-1和TLR-4的蛋白和/或mRNA水平发生改变，同时伴有动脉内皮细胞丢失。Dex治疗可逆转这些变化。相反，用育亨宾阻断AdR-α2会减弱Dex的益处。在体外，Dex可减少应激血清诱导的活性氧生成和内皮细胞凋亡，同时PAR-2、Bcl-2和细胞色素c蛋白水平发生有益变化。育亨宾可减弱这些作用。因此，α-肾上腺素能受体激活似乎可减轻接受FeCl诱导手术的小鼠的应激相关血栓形成，可能是通过负向调节PAR-2信号通路实现的。这些发现提示了一种针对TCVDs患者CPS相关血栓事件的潜在治疗策略。
