Department of Clinical Pharmacology Lab, Nanjing First Hospital, Nanjing Medical University, Jiangsu, 210001, PR China.
Department of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Jiangsu, 211100, PR China.
Chem Biol Interact. 2024 Nov 1;403:111230. doi: 10.1016/j.cbi.2024.111230. Epub 2024 Sep 5.
Vascular endothelial injury is closely related to the progression of various cardio-cerebrovascular diseases. Whether Human Urinary Kallidinogenase (HUK) has a protective effect on endothelial injury remains unclear. This study established an in vivo model of rat common carotid artery intima injury and an in vitro model of human umbilical vein endothelial cell (HUVECs) injury induced by hydrogen peroxide (HO). To explore the protective effect and mechanism of HUK on endothelial injury. In vivo, HUK can reduce the hyperplasia and lumen stenosis of rat common carotid artery after intimal injury, and promote the fluorescence expression of vWF in the common carotid artery. HUK also activated the Nrf2/HO-1 signaling pathway in rat common carotid artery tissue to reduce endothelial damage. In vitro, HUK can inhibit the HO-induced decline in HUVECs activity, improve the migration ability of HUVECs induced by HO, inhibit the apoptosis and necrosis of HUVECs and the generation of ROS, and regulate the expression of VEGFA, ET-1 and eNOS proteins related to endothelial function in cells. The Nrf2/HO-1 signaling pathway is activated, and the HO-1 specific inhibitor zinc porphyrin (ZnPP) can partially reverse the protective effect of HUK on HO-induced HUVECs injury in terms of cell migration, necrosis and oxidative stress. The Nrf2/HO-1 signaling pathway plays an important role in the regulation of migration, necrosis and oxidative stress of HUVECs cells. HUK has a protective effect on vascular endothelial injury. HUK can inhibit oxidative stress and apoptotic necrosis by activating Nrf2/HO-1 signaling pathway.
血管内皮损伤与多种心脑血管疾病的进展密切相关。人尿激肽原酶（HUK）是否对内皮损伤具有保护作用尚不清楚。本研究建立了大鼠颈总动脉内膜损伤的体内模型和过氧化氢（HO）诱导的人脐静脉内皮细胞（HUVECs）损伤的体外模型，以探讨 HUK 对内皮损伤的保护作用及其机制。在体内，HUK 可减少大鼠颈总动脉内膜损伤后血管的增生和管腔狭窄，并促进颈总动脉 vWF 的荧光表达。HUK 还可激活大鼠颈总动脉组织中的 Nrf2/HO-1 信号通路，减轻内皮损伤。在体外，HUK 可抑制 HO 诱导的 HUVECs 活性下降，改善 HO 诱导的 HUVECs 迁移能力，抑制 HUVECs 凋亡和坏死以及 ROS 的产生，并调节与内皮功能相关的 VEGFA、ET-1 和 eNOS 蛋白在细胞中的表达。Nrf2/HO-1 信号通路被激活，HO-1 特异性抑制剂锌卟啉（ZnPP）可部分逆转 HUK 对 HO 诱导的 HUVECs 损伤的保护作用，在细胞迁移、坏死和氧化应激方面。Nrf2/HO-1 信号通路在调节 HUVECs 细胞的迁移、坏死和氧化应激中起重要作用。HUK 对血管内皮损伤具有保护作用。HUK 可通过激活 Nrf2/HO-1 信号通路抑制氧化应激和凋亡坏死。
