Inflammation and Oxidative Stress Role of S100A12 as a Potential Diagnostic and Therapeutic Biomarker in Acute Myocardial Infarction

Abstract

Acute myocardial infarction (AMI) is one of the most serious cardiovascular diseases with high morbidity and mortality. Numerous studies have indicated that S100A12 may has an essential role in the occurrence and development of AMI, and in-depth studies are currently lacking. The purpose of this study is to investigate the effect of S100A12 on inflammation and oxidative stress and to determine its clinical applicability in AMI. Here, AMI datasets used to explore the expression pattern of S100A12 in AMI were derived from the Gene Expression Omnibus (GEO) database. The pooled standard average deviation (SMD) was calculated to further determine S100A12 expression. The overlapping differentially expressed genes (DEGs) contained in all included datasets were recognized by the GEO2R tool. Then, functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were carried out to determine the molecular function of overlapping DEGs. Gene set enrichment analysis (GSEA) was conducted to determine unrevealed mechanisms of S100A12. Summary receiver operating characteristic (SROC) curve analysis and receiver operating characteristic (ROC) curve analysis were carried out to identify the diagnostic capabilities of S100A12. Moreover, we screened miRNAs targeting S100A12 using three online databases (miRWalk, TargetScan, and miRDB). In addition, by comprehensively using enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR (RT–qPCR), Western blotting (WB) methods, etc., we used the AC16 cells to validate the expression and underlying mechanism of S100A12. In our study, five datasets related to AMI, GSE24519, GSE60993, GSE66360, GSE97320, and GSE48060 were included; 412 overlapping DEGs were identified. Protein-protein interaction (PPI) network and functional analyses showed that S100A12 was a pivotal gene related to inflammation and oxidative stress. Then, S100A12 overexpression was identified based on the included datasets. The pooled standard average deviation (SMD) also showed that S100A12 was upregulated in AMI ( SMD = 1.36 , 95% CI: 0.70-2.03, p = 0.024 ). The SROC curve analysis result suggested that S100A12 had remarkable diagnostic ability in AMI ( AUC = 0.90 , 95% CI: 0.87-0.92). And nine miRNAs targeting S100A12 were also identified. Additionally, the overexpression of S100A12 was further confirmed that it maybe promote inflammation and oxidative stress in AMI through comprehensive in vitro experiments. In summary, our study suggests that overexpressed S100A12 may be a latent diagnostic biomarker and therapeutic target of AMI that induces excessive inflammation and oxidative stress. Nine miRNAs targeting S100A12 may play a crucial role in AMI, but further studies are still needed. Our work provides a positive inspiration for the in-depth study of S100A12 in AMI.

The Correlation Between Cardiac Oxidative Stress and Inflammatory Cytokine Response Following Myocardial Infarction

“…TNF acts as the primary pro-inflammatory cytokine by directly activating sensory neurons through receptors, stimulating the synthesis of other pro-inflammatory cytokines, and inducing myocardial cell damage. 13 Myocardial infarction is characterized by a systemic pro-inflammatory state. The overexpression of TNF damages mitochondrial DNA, inhibits antioxidant factors, alters the activity of mitochondrial complex III, and consequently increases the production of ROS.…”

Expression pattern and diagnostic value of ferroptosis-related genes in acute myocardial infarction

“…It is reported that ITGAM is a key immune-related gene, which is significantly increased in blood samples of patients with AMI ( 25 ). S100A9 and S100A12 are up-regulated in the process of AMI and can induce macrophage/microglia inflammation ( 26 , 27 ). Shuangxinfang (psycho-cardiology formula, PCF) could inhibit this process and improve the heart function of mice with myocardial infarction ( 26 ).…”

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review

“…Finally, the active complex interacts with the 3′-UTR of target mRNA through complementary pairing of base pairings, causing translational repression or RNA degradation (Figure 1A). 83−85 Through this process, miRNAs were involved in a series of cellular processes, including apoptosis, 4−6 oxidative stress, 7 cell proliferation, 8,9 inflammation, 10,11 hematopoiesis, 4,12 and tumorigenesis. 13,14 Recent studies revealed that miRNAs not only have an intracellular function but also stably exist in biological fluids such as saliva, cerebrospinal fluid, plasma, serum, gingival fluid, and urine.…”

“…These functional miRNAs form the RISC via binding to AGO. Finally, the active complex interacts with the 3′-UTR of target mRNA through complementary pairing of base pairings, causing translational repression or RNA degradation (Figure A). − Through this process, miRNAs were involved in a series of cellular processes, including apoptosis, − oxidative stress, cell proliferation, , inflammation, , hematopoiesis, , and tumorigenesis. , …”

“…A particular miRNA can target various mRNAs to induce translational repression or RNA degradation, and one mRNA can be regulated by multiple different miRNAs . By modulating gene expression at the post-translational level, miRNAs play a critical role in a series of cellular processes, including apoptosis, − oxidative stress, cell proliferation, , inflammation, , hematopoiesis, , and tumorigenesis. , Importantly, miRNAs not only have an intracellular function but also stably exist in biological fluids such as saliva, cerebrospinal fluid, plasma, serum, gingival fluid, and urine. − Therefore, circulating miRNAs are considered biomarkers of disease and can regulate gene expression in distal cells or organs. ,, …”