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Targeting the E3 ligase RLIM to regulate VSMC phenotypic switching in vascular aging: implications for cold stress
Wenqian Jiang, Madi Guo, Xu Wang, Xin Liu, Yong Zhang
2025, 5(3): 147-156. doi: 10.1515/fzm-2025-0018
Keywords: arterial aging, vascular remodeling, ubiquitination, vascular smooth muscle cell, phenotypic switching
  Objective  Cold exposure may impair vascular function and promote cardiovascular diseases (CVDs) by causing vasoconstriction, hemodynamic changes, and sympathetic activation. Vascular aging, a key factor in CVDs, is linked to phenotypic switching of vascular smooth muscle cells (VSMCs), but its regulatory mechanisms are not fully understood.  Materials and methods  We used aged C57BL/6 mice and D-galactose-induced senescent VSMCs to investigate the role of the E3 ligase RLIM in arterial aging. RLIM knockdown and overexpression in vivo were achieved using adenoassociated virus (AAV) vectors. Vascular aging and stiffness were assessed using β-galactosidase staining, pulse wave velocity (PWV) measurements, and histological staining. Proteomic profiling was conducted to identify key protein alterations associated with vascular dysfunction and to elucidate underlying mechanisms.  Results  RLIM expression was significantly upregulated in the aortae of aged mice and D-galactose-induced senescent VSMCs. AAV-mediated RLIM knockdown significantly attenuated vascular aging, as evidenced by vascular ultrasound and histological assessments. Conversely, RLIM overexpression exacerbated vascular damage. Proteomic analysis revealed that RLIM knockdown in VSMCs from aged mice resulted in increased expression of smooth muscle contractile proteins and decreased levels of inflammatory markers, indicating a phenotypic shift toward a more contractile state.  Conclusion  These findings identify RLIM as a key regulator of arterial aging and a promising therapeutic target for age-related cardiovascular diseases.
Identification of hub genes and pathways in mouse with cold exposure
Xu Wang, Hongbo Hu, Ying Zhang
2024, 4(4): 233-241. doi: 10.1515/fzm-2024-0023
Keywords: cold exposure, hub genes, pathway, adipose tissue
  Background   Cold exposure is linked to numerous diseases, yet the changes in key genes and pathways in mice under cold exposure remain unexplored. Understanding these alterations could offer insights into the mechanisms of cold resistance and contribute valuable ideas for treating cold-related diseases.   Methods   The dataset GSE148361 was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the "limma" package in R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on DEGs. The STRING (Search Tool for the Retrieval of Interacting Genes) database was used to construct a protein-protein interaction (PPI) network. Additionally, gene set enrichment analysis (GSEA) was conducted to identify pathways associated with key genes. miRNAs and upstream transcription factors (TFs) were predicted using the miRNet database.   Results   A total of 208 DEGs were identified, with 137 upregulated and 71 downregulated. In biological processes, DEGs were enriched in nucleotide and purine-containing compound metabolism. For cellular components, DEGs were involved in condensed chromosomes and mitochondrial protein complexes. In molecular functions, proton transmembrane transporter activity was enriched. KEGG pathway analysis showed significant enrichment in biosynthesis of unsaturated fatty acids, fatty acids, and pyruvate metabolism. From the PPI network, 12 hub genes were identified using MCODE. Four hub genes (Col3a1, fi203, Rtp4, Vcan) demonstrated similar trends in a validation set (GSE110420) and were significantly differentially expressed. GSEA analysis indicated that these four genes were enriched in pathways such as ECM-receptor interaction and cytokinecytokine receptor interaction. The hub gene network included 93 miRNAs and one TF.   Conclusion   This study identified four hub genes as potential diagnostic biomarkers for cold exposure, providing insights for further research on the effects of cold on gene expression and disease.