ABSTRACT
Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD+ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD+ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.
Subject(s)
Cardiovascular Diseases , Muscle, Smooth, Vascular , Humans , Animals , Mice , Cellular Senescence/genetics , Cardiovascular Diseases/metabolism , NAD/metabolism , Cells, Cultured , Aging/physiology , Arteries , Myocytes, Smooth Muscle/metabolismABSTRACT
Atherosclerotic plaques belong to the common vascular disease in the aged, which rupture will lead to acute thromboembolic diseases, the leading cause of fatal cardiovascular events. Accumulating evidence indicates that the lncRNAs-miRNAs-mRNA regulatory network plays a critical role in atherosclerosis. Based on RNA sequencing (GSE207252), we constructed expression profiles of lncRNAs, microRNAs, and mRNA in the carotid plaque of atherosclerosis patients and analyzed differentially expressed genes (DEGs). We identified three candidate lncRNAs using two algorithms (LASSO and SVM-RFE): lnc_GLRX3, lnc_FGF7-5, and DISC1FP1). LNCipedia, TargetScan, and miRDB databases were used to predict target miRNAs of lncRNAs and target genes of miRNAs. Gene ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA) analysis of DEGs was carried out using the R package clusterProfiler. A PPI network was constructed using the STRING website and visualized by Cytoscape. According to the "MCC" method of the plug-in cytoHubba in Cytoscape, ERCC4 was the top hub gene of the PPI network. We constructed a lncRNA_FGF7-5/lncRNA_GLRX3-miR-2681-5p-ERCC4 regulatory network for carotid plaque using lncRNA-miRNA and miRNA-mRNA pairs. Next, lncRNA_FGF7-5 and lncRNA_GLRX3 targeted miR-2681-5p directly to upregulate ERCC4 expression. Silencing of lncRNA_FGF7-5 and lncRNA_GLRX3 promoted apoptosis and TP53 expression in HUVECs treated with ox-LDL; however, these effects were reversed by ERCC4-overexpression. Taken together, these findings indicated that lncRNA_FGF7-5 and lncRNA_GLRX3 together reduced atherosclerosis-induced apoptosis of HUVECs via targeting miR-2681-5p to increase ERCC4 expression, thereby preventing the formation of carotid plaque and finally inhibiting atherosclerosis progression.
Subject(s)
Atherosclerosis , MicroRNAs , Plaque, Atherosclerotic , RNA, Long Noncoding , Humans , Aged , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Plaque, Atherosclerotic/genetics , Gene Regulatory Networks , MicroRNAs/genetics , MicroRNAs/metabolism , Atherosclerosis/genetics , RNA, Messenger/genetics , Carrier Proteins/genetics , Fibroblast Growth Factor 7/genetics , Fibroblast Growth Factor 7/metabolismABSTRACT
Glioma, especially high-grade glioma, is highly malignant with high rate of recurrence and poor prognosis. The mechanisms of glioma progression and recurrence have not been elucidated. Previous studies showed that long non-coding RNAs (lncRNAs) involved in the development and progression of glioma. However, the roles of lncRNAs in the recurrence of glioma remain unknown. We use high throughput microarray to screen the differentially expressed lncRNAs and mRNAs in recurrence gliomas compared with primary gliomas. We found a total of 1,111 lncRNAs were differentially expressed in recurrent group. Among these, 639 lncRNAs were up-regulated, while 472 lncRNAs were down-regulated (fold Change ≥2.0). GO (Gene ontology) and pathway analysis revealed that the potential functions of differentially expressed lncRNAs were closely connected with the processes of cancer progression and pathogenesis. LncRNA classification and subgroup analysis further identified three important clusters of differentially expressed lncRNA-mRNA pairs which have potential gene regulatory functions. This study for the first time showed abundant differentially expressed lncRNAs in recurrent gliomas. Some lncRNAs may play important roles in glioma recurrence, such as previously reported H19, CRNDE, HOTAIRM1 or unreported AC016745.3, XLOC_001711, RP11-128A17.1. Moreover, this study set a basis for future researches on specific lncRNA which may contribute to the recurrence of glioma. Further studies on these lncRNAs will help to elucidate the mechanism of glioma recurrence at genetic level and find therapeutic targets for glioma patients.