ABSTRACT
Atherosclerosis (AS) represents a prevalent initiating factor for cardiovascular events. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is an oncofetal RNA-binding protein that participates in cardiovascular diseases. This work aimed to elaborate the effects of IGF2BP3 on AS and the probable mechanism by using an oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) model. Results indicated that IGF2BP3 expression was declined in the blood of AS patients and ox-LDL-induced HUVECs. IGF2BP3 elevation alleviated ox-LDL-provoked viability loss, apoptosis, oxidative DNA damage and endothelial dysfunction in HUVECs. Moreover, IGF2BP3 bound SESN1 and stabilized SESN1 mRNA. Furthermore, SESN1 interference reversed the impacts of IGF2BP3 overexpression on the apoptosis, oxidative DNA damage and endothelial dysfunction of ox-LDL-challenged HUVECs. Additionally, the activation of Nrf2 signaling mediated by IGF2BP3 up-regulation in ox-LDL-treated HUVECs was blocked by SESN1 absence. Collectively, SESN1 stabilized by IGF2BP3 might protect against AS by activating Nrf2 signaling.
Subject(s)
Human Umbilical Vein Endothelial Cells , Lipoproteins, LDL , NF-E2-Related Factor 2 , Oxidative Stress , RNA, Messenger , RNA-Binding Proteins , Signal Transduction , Humans , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/drug effects , Lipoproteins, LDL/pharmacology , Lipoproteins, LDL/metabolism , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Oxidative Stress/drug effects , Signal Transduction/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , Apoptosis/drug effects , Atherosclerosis/metabolism , Atherosclerosis/genetics , Atherosclerosis/pathology , RNA Stability/drug effects , DNA Damage , SestrinsABSTRACT
BACKGROUND: Atherosclerosis (AS) is a disease characterized by the disorder of lipid metabolism and the formation of atherosclerotic plaques in the arterial wall, leading to arterial stenosis. Sestrins 1 (SESN1) plays an important regulatory role in AS, but the specific regulatory mechanism is still unclear. METHODS: ApoE-/- mouse models of AS were constructed. After overexpressing SESN1, oil red O staining was used to detect the degree of aortic plaque. HE staining detected the endothelial damage of the surrounding tissues. ELISA was used to detect the levels of vascular inflammation and oxidative stress. The iron metabolism in vascular tissues was detected by immunofluorescence. The expressions of SESN1 and ferroptosis-related proteins were detected by western blot. In the oxidized low-density lipoprotein (ox-LDL)-induced injury model in human umbilical vein endothelial cells (HUVECs), CCK8, ELISA, immunofluorescence and western blot were respectively used to detect cell viability, inflammatory response, oxidative stress and ferroptosis. The regulatory mechanism of SESN1 on endothelial ferroptosis in AS was further explored following the addition of P21 inhibitor UC2288. RESULTS: Overexpression of SESN1 could inhibit the extent of the plaque and reduce the endothelial injury of plaque tissues in AS mice. In both mouse and cell models of AS, SESN1 overexpression inhibited inflammatory response, oxidative stress response, and endothelial ferroptosis. The inhibitory effect of SESN1 on endothelial ferroptosis might be achieved through activation of P21. CONCLUSION: SESN1 overexpression plays an inhibitory role in vascular endothelial ferroptosis through the activation of P21 in AS.
