Identification and validation of senescence-related genes in circulating endothelial cells of patients with acute myocardial infarction

BackgroundAcute myocardial infarction (AMI) is the main clinical cause of death and cardiovascular disease and thus has high rates of morbidity and mortality. The increase in cardiovascular disease with aging is partly the result of vascular endothelial cell senescence and associated vascular dysfunction. This study was performed to identify potential key cellular senescence-related genes (SRGs) as biomarkers for the diagnosis of AMI using bioinformatics.MethodsUsing the CellAge database, we identified cellular SRGs. GSE66360 and GSE48060 for AMI patients and healthy controls and GSE19322 for mice were downloaded from the Gene Expression Omnibus (GEO) database. The GSE66360 dataset was divided into a training set and a validation set. The GSE48060 dataset was used as another validation set. The GSE19322 dataset was used to explore the evolution of the screened diagnostic markers in the dynamic process of AMI. Differentially expressed genes (DEGs) of AMI were identified from the GSE66360 training set. Differentially expressed senescence-related genes (DESRGs) selected from SRGs and DEGs were analyzed using Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein-protein interaction (PPI) networks. Hub genes in DESRGs were selected based on degree, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. Finally, a miRNA-gene network of diagnostic genes was constructed and targeted drug prediction was performed.ResultsA total of 520 DEGs were screened from the GSE66360 training set, and 279 SRGs were identified from the CellAge database. The overlapping DEGs and SRGs constituted 14 DESRGs, including 4 senescence suppressor genes and 10 senescence inducible genes. The top 10 hub genes, including FOS, MMP9, CEBPB, CDKN1A, CXCL1, ETS2, BCL6, SGK1, ZFP36, and IGFBP3, were screened. Furthermore, three diagnostic genes were identified: MMP9, ETS2, and BCL6. The ROC analysis showed that the respective area under the curves (AUCs) of MMP9, ETS2, and BCL6 were 0.786, 0.848, and 0.852 in the GSE66360 validation set and 0.708, 0.791, and 0.727 in the GSE48060 dataset. In the GSE19322 dataset, MMP9 (AUC, 0.888) and ETS2 (AUC, 0.929) had very high diagnostic values in the early stage of AMI. Finally, based on these three diagnostic genes, we found that drugs such as acetylcysteine and genistein may be targeted for the treatment of age-related AMI.ConclusionThe results of this study suggest that cellular SRGs might play an important role in AMI. MMP9, ETS2, and BCL6 have potential as specific biomarkers for the early diagnosis of AMI

PON2 ameliorates Ang II‐induced cardiomyocyte injury by targeting the CANX/NOX4 signaling pathway

Abstract Background The incidence of heart failure (HF) presents an escalating trend annually, second only to cancer. Few literatures are available regarding on the role of paraoxonase 2 (PON2) in HF so far despite the protective role of PON2 in cardiovascular diseases. Methods PON2 expression in AC16 cells was examined with reverse transcriptase‐quantitative polymerase chain reaction and western blot following angiotensin II (Ang II) challenging. After PON2 elevation, 2, 7‐dichlorofluorescein diacetate assay estimated reactive oxygen species content, related kits appraised oxidative stress, enzyme‐linked immunosorbent assay evaluated inflammatory levels, and Western blot was applied to the analysis of apoptosis levels. Research on cytoskeleton was conducted by immunofluorescence (IF), and Western blot analysis of the expressions of hypertrophy‐related proteins was performed. BioGRID and GeneMania databases were used to analyze the relationship between PON2 and Calnexin (CANX), which was corroborated by co‐immunoprecipitation experiment. Subsequently, PON2 and CANX were simultaneously overexpressed in AC16 cells induced by Ang II to further figure out the mechanism. Results PON2 expression was depleted in Ang II‐induced AC16 cells. PON2 might mediate CANX/NOX4 signaling to inhibit oxidation, inflammatory, hypertrophy, and damage in Ang II‐induced AC16 cells. Conclusion PON2 can ease Ang II‐induced cardiomyocyte injury via targeting CANX/NOX4 signaling