Department of Cardiovascular Medicine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming, Yunnan 650032, P.R.China.
Department of Cardiovascular Medicine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming, Yunnan 650032, P.R.China; Faculty of Life Science and Technology, Kunming University of Science and Technology, No.727 Jingming South Road, Kunming 650500, P.R.China.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):113131. doi: 10.1016/j.intimp.2024.113131. Epub 2024 Sep 13.
Abnormalities in iron and lipid metabolism are recognized as key contributors to atherosclerosis (AS). Therefore, this study proposes to characterize the biomarker related to iron and lipid metabolism in AS using bioinformatics, animal, and cell experiments.
The limma package was utilized to identify differentially expressed genes (DEGs) in GSE70126 and GSE70619 datasets, and biomarkers were screened using enrichment analysis and PPI networks. IFIT2 was knocked down using shRNA lentivirus in a high fat diet (HFD)-induced APOE AS model to investigate its effects of IFIT2 on the pathology, iron retention, and lipid accumulation. Iron storage-related and cholesterol efflux-related proteins were evaluated following exogenous modulation of IFIT2 expression in ox-LDL-induced foamy macrophages.
Compared to non-foamy macrophages from the aorta, 189 and 4152 DEGs were identified in foamy macrophages within the GSE70126 and GSE70619 datasets, respectively. Moreover, intersecting DEGs may modulate immune responses, cell adhesion, vascular permeability, and oxidative stress through NF-kappa B, Wnt, TNF and HIF-1 signaling pathways. Notably, IFIT2 was significantly upregulated in foamy macrophages and AS models. In vivo, IFIT2 co-localized with foamy macrophages, and its knockdown led to reductions in plasma lipid levels, plaque area, immune infiltration, iron retention, and lipid accumulation. In vitro, IFIT2 knockdown alleviated the ox-LDL-induced increase in iron storage-related proteins (Ferritin-L and Ferritin-H) and iron (Fe and Fe) in foamy macrophages. Furthermore, IFIT2 knockdown reduced lipid accumulation and upregulated cholesterol efflux-related proteins (PPARγ, LXRα, ABCA1, and ABCG1) in foamy macrophages.
IFIT2 knockdown attenuates iron retention and lipid accumulation in AS plaques, and facilitated cholesterol efflux from foamy macrophages via the PPARγ/LXRα/ABCA1-ABCG1 pathway.
铁代谢和脂质代谢异常被认为是动脉粥样硬化（AS）的关键因素。因此，本研究拟采用生物信息学、动物和细胞实验来研究与 AS 中铁和脂质代谢相关的生物标志物。
利用 limma 软件包分析 GSE70126 和 GSE70619 数据集，采用富集分析和 PPI 网络筛选差异表达基因（DEGs）。构建高脂肪饮食（HFD）诱导的 APOE AS 模型，利用 shRNA 慢病毒敲低 IFIT2，研究 IFIT2 对 AS 病理、铁蓄积和脂质蓄积的影响。通过外源性调节 IFIT2 表达，观察其对 ox-LDL 诱导泡沫巨噬细胞中铁蓄积相关和胆固醇流出相关蛋白的影响。
与主动脉非泡沫巨噬细胞相比，GSE70126 和 GSE70619 数据集中泡沫巨噬细胞中分别鉴定出 189 个和 4152 个 DEGs。此外，交集 DEGs 可能通过 NF-kappa B、Wnt、TNF 和 HIF-1 信号通路调节免疫反应、细胞黏附、血管通透性和氧化应激。值得注意的是，IFIT2 在泡沫巨噬细胞和 AS 模型中显著上调。体内研究显示，IFIT2 与泡沫巨噬细胞共定位，敲低 IFIT2 可降低血浆脂质水平、斑块面积、免疫浸润、铁蓄积和脂质蓄积。体外研究显示，IFIT2 敲低可减轻 ox-LDL 诱导的泡沫巨噬细胞中铁蓄积相关蛋白（Ferritin-L 和 Ferritin-H）和铁（Fe 和 Fe）含量增加。此外，IFIT2 敲低可减少泡沫巨噬细胞中的脂质蓄积，并上调胆固醇流出相关蛋白（PPARγ、LXRα、ABCA1 和 ABCG1）。
IFIT2 敲低可减轻 AS 斑块中的铁蓄积和脂质蓄积，并通过 PPARγ/LXRα/ABCA1-ABCG1 通路促进泡沫巨噬细胞中的胆固醇流出。
