Department of Cardiovascular Medicine, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
Department of Cardiovascular Medicine, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
Nutr Metab Cardiovasc Dis. 2021 Nov 29;31(12):3508-3521. doi: 10.1016/j.numecd.2021.08.031. Epub 2021 Aug 13.
LncRNA plasmacytoma variant translocation 1 (PVT1) plays a regulatory role in some cardiovascular diseases, but its role in atherosclerosis (AS) remains barely explored. The study aimed to investigate the effects of PVT1 on high fat diet-induced AS and its potential mechanisms.
ApoE -/- mice were fed with high fat diet for 8 weeks to establish an AS model. Lentiviral vectors containing PVT1 short hairpin RNA (PVT1-shRNA) or NC-shRNA were administered by tail vein injection. Cell viability, apoptosis, inflammatory factor secretion, and cellular oxidative stress were measured to evaluate oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cell (HUVEC) injury. Dual-luciferase reporter gene and RNA immunoprecipitation assays were used to confirm the interaction between miR-153-3p and PVT1 or growth factor receptor binding protein 2 (GRB2). Atherosclerotic lesions, lipid deposition, and cell apoptosis in aorta were analyzed by H&E, Oil Red O, and TUNEL straining. PVT1 knockdown alleviated ox-LDL-induced inflammation, apoptosis and oxidative stress in HUVECs. PVT1 acted as a sponge of miR-153-3p, and GRB2 was confirmed as a target of miR-153-3p. MiR-153-3p overexpression attenuated the enhanced effects of PVT1 on ox-LDL-induced cell damage. GRB2 overexpression reversed the mitigating effects of miR-153-3p on ox-LDL-caused injury. Inhibiting PVT1 restrained the activation of ERK1/2 and p38 pathway via miR-153-3p/GRB2 axis. Additionally, silencing PVT1 in vivo reduced atherosclerotic plaques, lipid deposition, inflammation, oxidative stress, and apoptosis in AS mice.
PVT1 knockdown alleviated ox-LDL-induced vascular endothelial cell injury and atherosclerosis through miR-153-3p/GRB2 axis via ERK1/2 and p38 pathway.
长链非编码 RNA 浆细胞瘤变异易位 1（PVT1）在一些心血管疾病中发挥着调控作用，但它在动脉粥样硬化（AS）中的作用仍鲜有研究。本研究旨在探讨 PVT1 对高脂饮食诱导的 AS 的影响及其潜在机制。
采用腹腔注射载脂蛋白 E 基因敲除（ApoE-/-）小鼠高脂饲料 8 周建立 AS 模型，尾静脉注射慢病毒载体携带的 PVT1 短发夹 RNA（PVT1-shRNA）或阴性对照 shRNA（NC-shRNA）。通过细胞活力、细胞凋亡、炎症因子分泌和细胞氧化应激来评估氧化型低密度脂蛋白（ox-LDL）诱导的人脐静脉内皮细胞（HUVEC）损伤。双荧光素酶报告基因和 RNA 免疫沉淀实验用于证实 miR-153-3p 与 PVT1 或生长因子受体结合蛋白 2（GRB2）之间的相互作用。通过 H&E、油红 O 和 TUNEL 染色分析主动脉粥样硬化病变、脂质沉积和细胞凋亡。PVT1 敲低减轻了 ox-LDL 诱导的 HUVEC 炎症、凋亡和氧化应激。PVT1 作为 miR-153-3p 的海绵，GRB2 被确认为 miR-153-3p 的靶基因。miR-153-3p 过表达减弱了 PVT1 对 ox-LDL 诱导的细胞损伤的增强作用。GRB2 过表达逆转了 miR-153-3p 对 ox-LDL 引起的损伤的缓解作用。通过 miR-153-3p/GRB2 轴抑制 PVT1 抑制了 ERK1/2 和 p38 通路的激活。此外，体内沉默 PVT1 可减少 AS 小鼠的动脉粥样硬化斑块、脂质沉积、炎症、氧化应激和细胞凋亡。
沉默 PVT1 通过 miR-153-3p/GRB2 轴抑制 ERK1/2 和 p38 通路减轻 ox-LDL 诱导的血管内皮细胞损伤和动脉粥样硬化。
