Lipoxin A4 restores oxidative stress-induced vascular endothelial cell injury and thrombosis-related factor expression by its receptor-mediated activation of Nrf2-HO-1 axis

摘要

Venous thromboembolism (VTE) constitutes a common cause of hospital-related morbidity and mortality, with the proverbial clinical feature of deep venous thrombosis (DVT). Endothelial cell injury and dysfunction comprise the critical contributor for the development of DVT. Lipoxin A4 (LXA4) fulfills pleiotropic roles in injury repair. However, its role in DVT remains poorly elucidated. In the present study, LXA4 supplementation dampened H2O2-evoked cytotoxic injury in human umbilical vein endothelial cells (HUVECs) by increasing cell viability, suppressing cell apoptosis and caspase-3 activity. Moreover, treatment with LXA4 afforded cytoprotective effects against oxidative stress damage in response to H2O2 by abrogating ROS, lactate dehydrogenase (LDH) and MDA leakage, and elevating anti-oxidant SOD levels. Notably, LXA4 administration attenuated pro vasoconstriction factor endothelin-1(ET-1) expression in HUVECs exposed to H2O2, but enhanced the productions of vasodilatation factor NO and prostacyclin (PGI2). Simultaneously, H2O2-induced high expression of pro thrombotic Von Willebrand Factor (vWF) was also inhibited by LXA4. Mechanism analysis substantiated that LXA4 further augmented activation of the Nrf2-HO-1 pathway. Nevertheless, blocking this signaling via si-Nrf2 transfection or HO-1 antagonist ZnPP both reversed LXA4-mediated effects against oxidative stress injury and thrombotic potential. Cessation of the LXA4 receptor pathway by its inhibitor Boc2 not only counteracted LXA4-evoked activation of the Nrf2-HO-1, but also reversed LXA4-mediated anti-oxidative stress and thrombosis related factor expression. Accordingly, this study suggests that LXA4 may ameliorate vascular endothelial cell oxidative stress injury and subsequent thrombotic response via LXA4 receptor-dependent activation of the Nrf2-HO-1 signaling, implying a promising strategy for DVT and its complication.