Abstract 4139632: Narciclasine Reverses Vascular Aging and Atherosclerosis by Suppressing SPP1-mediated Inflammation Signals

Objective: The senescence of smooth muscle is one of the significant risk factors in atherosclerosis progression in which the vascular inflammation plays an important role on dysfunction. This study is designed to explore the novel vascular aging inflammation biomarkers and screen the potential molecular interventional targets through bioinformatic analysis. Methods&Results: The transcriptional analysis on GSE16487 database from 15 human vascular tissue samples, 8 from less than 60 yro (young group) and 7 from older than 75 yro (Aged group). The comparison between two groups contained 252 (114 upregulated and 138 downregulated) DEGs with minimum 1.5-fold change. As shown in FigA-B, 114 upregulated genes were mainly involved in 5 biological processes and 5 signaling pathways using GO and KEGG functional enrichment analysis. PPI network results indicated that 9 genes had interactions at medium confidence (score＞0.415), which are mainly included the GO and KEGG inflammation-related terms leukocyte cell-cell adhesion, Cytokine-cytokine receptor interaction, TGF-beta signaling pathway and regulation of T cell activation (Fig C). Furthermore, the association between 9 genes and vascular aging was validated in an independent cohort (GSE117715, GSE116277, GSE130727) and senescent VSMCs induced by 250 μM oleic acid (OA). ssGSEA analysis results revealed a higher abundance of Tem and Th2 cells within aged vascular tissues, indicating that the local inflammation activated the immune system and immune cell recruitment (p<0.05) (Fig D). To further screen novel therapeutics, all DEGs expression data were uploaded to CMap database. The results showed that narciclasine, known as RhoA activator, may alleviate inflammation-related vascular aging by regulating SPP1-mediated cytokines release(Fig E-G). In vitro experiments demonstrated that narciclasine alleviated senescence of VSMCs(p<0.05). In vivo experiments revealed that narciclasine treatment reduced aortic plaque area and diminished lipid core size within atherosclerotic plaques in ApoE -/- mice fed a high-fat diet(p<0.05). Conclusion: The 9 inflammatory biomarkers were screened and validated in senescent VSMCs. The compound narciclasine can regulate SPP1-mediated cytokines release to suppress inflammation signals and alleviate vascular aging. This research explores potential inflammation-related biomarkers and interventional targets for alleviating vascular aging.