He Chengjian, Song Xiaojing, Zhu Zigui, Xiao Yan, Chen Jiacheng, Yao Hongyi, Xie Rongjun
Affiliated Nanhua Hospital, University of South China, No. 336, Dongfeng South Road Zhuhui District, Hengyang City, Hunan Province, China.
J Thromb Thrombolysis. 2025 Jan;58(1):84-95. doi: 10.1007/s11239-024-03029-3. Epub 2024 Aug 23.
Ghrelin exerts widespread effects in several diseases, but its role and mechanism in Acute Traumatic Coagulopathy (ATC) are largely unknown. The effect of ghrelin on cell proliferation was examined using three assays: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), Lactate Dehydrogenase (LDH), and flow cytometry. The barrier function of the endothelial cells was evaluated using the Trans-Endothelial Electrical Resistance (TEER) and the endothelial permeability assay. An ATC mouse model was established to evaluate the in vivo effects of ghrelin. The Ras homolog family member A (RhoA) overexpression plasmid or adenovirus was used to examine the molecular mechanism of ghrelin. Ghrelin enhanced Human Umbilical Vein Endothelial Cells (HUVEC) proliferation and endothelial cell barrier function and inhibited HUVEC permeability damage in vitro. Additionally, ghrelin decreased the activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) in mice blood samples in the ATC mouse model. Ghrelin also improved the pathological alterations in postcava. Mechanistically, ghrelin acts through the RhoA/ Rho-associated Coiled-coil Containing Kinases (ROCK)/ Myosin Light Chain 2 (MLC2) pathway. Furthermore, the protective effects of ghrelin, both in vitro and in vivo, were reversed by RhoA overexpression. Our findings demonstrate that ghrelin may reduce vascular endothelial cell damage and endothelial barrier dysfunction by blocking the RhoA pathway, suggesting that ghrelin may serve as a potential therapeutic target for ATC treatment.
胃饥饿素在多种疾病中发挥着广泛作用，但其在急性创伤性凝血病（ATC）中的作用及机制尚不清楚。采用三种检测方法研究胃饥饿素对细胞增殖的影响：3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2-H-四氮唑溴盐（MTT）法、乳酸脱氢酶（LDH）法和流式细胞术。采用跨内皮电阻（TEER）和内皮通透性检测评估内皮细胞的屏障功能。建立ATC小鼠模型以评估胃饥饿素的体内作用。使用Ras同源家族成员A（RhoA）过表达质粒或腺病毒研究胃饥饿素的分子机制。胃饥饿素可增强人脐静脉内皮细胞（HUVEC）增殖和内皮细胞屏障功能，并在体外抑制HUVEC通透性损伤。此外，在ATC小鼠模型中，胃饥饿素可降低小鼠血液样本中活化部分凝血活酶时间（aPTT）和凝血酶原时间（PT）。胃饥饿素还改善了后腔静脉的病理改变。机制上，胃饥饿素通过RhoA/含Rho相关卷曲螺旋的蛋白激酶（ROCK）/肌球蛋白轻链2（MLC2）途径发挥作用。此外，RhoA过表达可逆转胃饥饿素在体外和体内的保护作用。我们的研究结果表明，胃饥饿素可能通过阻断RhoA途径减少血管内皮细胞损伤和内皮屏障功能障碍，提示胃饥饿素可能成为ATC治疗的潜在靶点。
