In the present study, through analysing the COPD dataset (GSE38974) and the AMI dataset (GSE60993) from GEO, we found 65 common DEGs between these diseases. GO enrichment and KEGG pathway enrichment analyses were performed on the Metascape, and a PPI network was constructed to identify the top 5 hub genes from among the 65 common DEGs. These 5 genes may have important regulatory roles in COPD and AMI. The results of the present study may be beneficial for understanding the relationship between COPD and AMI.
In our study, GO enrichment analysis showed that common DEGs were mostly enriched in inflammation or apoptotic biological processes, such as intrinsic apoptotic signaling pathway, regulation of inflammatory response and immune response-regulating signaling pathway. Common DEGs in the KEGG pathway were mostly enriched in apoptosis, cytokine-cytokine receptor interaction, TNF signaling pathway, MAPK signaling pathway and HIF-1 signaling pathway. The results implied that above biological processes and pathways might acted important roles in COPD and AMI. Chronic inflammation affected predominantly the lung parenchyma and peripheral airways that resulted in largely irreversible and progressive airflow limitation during the process of COPD. Inflammation is significant in the pathophysiology of atherosclerosis and of acute coronary syndromes and inflammatory activity in the vessel wall act important roles in plaque instability in AMI. Therapeutic interventions in vivo implied that targeted inhibition of specific inflammatory signals protected the heart from acute infarcted injury and prevented adverse remodelling following MI. Bronchial epithelial cells apoptosis is increased in COPD and contributed to the pathogenesis of COPD. Ischemia hypoxia induces cardiomyocyte (CM) apoptosis in the process of AMI. It has been reported that cytokine-cytokine receptor interaction was a significant pathway in COPD and AMI[24, 32]. Compared with healthy controls, TNF-α level was increased in COPD patients and higher TNF-α levels were induced by illness progression . Inhibiting the inflammatory response by targeting TNF-α might be a potential therapeutic target for COPD. TNF-α is a major predictor of mortality and new-onset heart failure in patients with AMI. TNF-α antagonism ameliorates myocardial ischemia-reperfusion(I/R) injury in mice. Compared with treatment with topical agents, use of TNF inhibitors for psoriasis was associated with a significant reduction in MI incident rate and risk . Convincing evidence confirms a central role of HIF-1 in mammalian oxygen homeostasis. With regard to the HIF-1 signaling pathway in COPD, increased expression of HIF-1, VEGF and VEGFR2 reflected the disease severity of COPD. HIF-1 attenuated progression of cardiac dysfunction after MI and reduced infarction in the mouse. Suppression of PHD2/HIF-1α/MAPK signaling pathway with NaHS may prevent emphysema, and subsequently inflammation, epithelial cell injury and apoptosis, and may be a novel strategy for the treatment of COPD. AMI was accompanied by endoplasmic reticulum stress, probably involving the MAPK signaling pathway and SB203580, a specific inhibitor of the MAPK signaling pathway, could relieve CM apoptosis and protect the myocardium by suppressing such stress.
Our results were in accordance with previous studies.
In the PPI network of 65 overlapping DEGs in AMI and COPD, MMP9, SOCS3, MCL1, ERBB2 and S100A12 were identified as the hub genes using the degree method in cytoHubba. In addition, function annotations of the 5 hub genes were performed and were similar to the enrichment results of all 65 common DEGs. MMPs, also called matrixins, are zinc-dependent endopeptidases known for their ability to cleave one or several extracellular matrix (ECM) constituents. MMP9, one of the most complex forms of matrix metalloproteinases, has the ability to degrade the ECM components and has significant role in the pathophysiological functions. MMP9 uniquely mediates pulmonary inflammation through augmentation of inflammation, neutrophil chemotaxis, and extracellular matrix degradation . In the sever or very severe COPD patients, the mRNA levels of MMP9 increased compared to non-COPD smokers or moderate COPD patients. Serum MMP9 is elevated in men with a history of MI and increased serum MMP9 may reflect inflammatory pathologic processes that are involved in the progression of atherosclerosis. The SOCS family are responsible for preventing excessive cytokine signaling, including a group of eight proteins . Among the different SOCS proteins, SOCS3 has received special attention and its dysfunction may be related with several diseases, including vascular inflammatory diseases, inflammatory bowel disease, cancers. SOCS3 played important roles in COPD and was involved in JAK/STAT signaling pathway. SOCS3 was significantly decreased in COPD at the transcriptional level and inhibition of SOCS3 mRNA expression may be associated with the dysbalance of cytokine signaling in COPD. SOCS3 has also been identified as a key gene in AMI according to previous studies[52, 53]. SOCS3 increased in the vast majority of patients in the first days of MI . The mRNA expression levels of the SOCS3 gene in AMI patients was 1.33-fold higher than that in the stable coronary artery disease patients, and the level of the SOCS3 protein was 1.25-fold higher. B-cell lymphoma-2 (BCL2) family proteins, comprising proapoptotic proteins (Bax and Bak), antiapoptotic proteins (BCL2, BCL-XL, BCL-w, MCL1, and A1) and BCL-2 homology domain 3 (BH3)-only proteins (Bid, Noxa, and Puma), have long been identified as pivotal apoptosis regulators. MCL1 is a crucial antiapoptotic member of the BCL-2 family and plays a key role in promoting cell survival. Unstimulated neutrophils from COPD patients had significantly higher expressions of MCL1 mRNA than cells from healthy controls and MCL1 mRNA expressions were significantly negatively correlated with the FEV1/FVC ratio and predicted FEV1 . A recent study demonstrated that chronic adaption to oxidative stress and up-regulation of MCL1 altered microbicidal function and mitochondrial metabolism, reducing the delayed phase of intracellular bacterial clearance in COPD. Animal experiments showed that MCL1 was up-regulated in the early stage of rat MI. miR-302 mediates hypoxia-reoxygenation-induced CM death by regulating MCL1 expression. In SOCS3-CKO mice, myocardial apoptosis was prevented and the expression of MCL1 was augmented in myocardial efficacy injury. ERBB2, also known as HER2 (Human Epidermal Growth Factor Receptor 2), CD340, and Neu protooncogene, is a member of the epidermal growth factor receptor (EGRF) family. It has been reported that ERBB2 was activated in smokers and patients with COPD suggests that targeting ERBB2 with currently available inhibitors might be beneficial in reducing epithelial injury and pulmonary dysfunction caused by CS. The mRNA expression of ERBB2 receptors was significantly down-regulated in the left ventricle of MI compared with the normal left ventricle. PTP-PEST contributed to part of the damages resulting from myocardial I/R and Auranofin, potentially acting through the PTP-PEST- ERBB2 signalling axis, reduced myocardial I/R injury. S100 proteins are Ca2+-binding proteins exclusively expressed in vertebrates in a cell-specific manner and they might regulate a variety of functions acting as intracellular Ca2 + sensors transducing the Ca2 + signal and extracellular factors affecting cellular activity via ligation of a battery of membrane receptors. Expression of S100A12 by monocytes/macrophages and neutrophils induces proinflammatory responses via ligation with the receptor for advanced glycation end-products (RAGE) and subsequent activation of intracellular signal transduction pathways . S100A12 was identified to regulate injury and inflammation of the lung, and play key roles in the pathogenesis of COPD. S100A12 activated airway epithelial cells to produce MUC5AC, which was known to contribute to severe muco-obstructive lung diseases worsening COPD pathogenesis [64, 65]. S100A12 is also involved in inflammatory cardiovascular disease and could be a novel biomarker for predicting cardiovascular events . A gene-by-gene analysis of the platelet gene expression identified that S100A12 increased in the AMI patients when compared to the healthy controls. These studies illustrated that MMP9, SOCS3, MCL1, ERBB2 and S100A12 played import roles in both COPD and AMI. Furthermore, we found that the expression of MMP9, SOCS3, MCL1, ERBB2 and S100A12 were significantly associated with a diagnosis efficacy of COPD and AMI using the area under the ROC curve (AUC). We also validated the relationship between the five hub genes and these two diseases in the CTD database.
In addition, we further analyzed the TFs corresponding to hub genes in AMI and COPD. We found that ELK1, ETV4, STAT3 and TFAP2A were significant TFs, which interacted with the hub genes. TF ELK1 has been found to act a carcinogenic role in human cancers, like hepatocellular carcinoma, thyroid cancer, breast cancer. Jennifer T Cairns etal. have proved that human lung epithelial cells and murine lung slices to CS extract demonstrated reduction of ELK1. Endothelial cells (ECs) apoptosis contributes the initiation and progression of atherosclerosis, which involves the development of AMI. miR-150 expression was substantially up-regulated during the oxidized low-density lipoprotein-induced apoptosis in ECs via targeting ELK1. It has been reported that ELK1 knockdown was sufficient to block ascites-induced MCL1 expression in ovarian cancer cells. ETV4 belongs to the E26 transformation-specific (ETS) family and has been found to be overexpressed in multiple cancers. Overexpression of NRP2 induced expression of the TF ETV4 and ERK MAP kinase, leading to enhanced MMP2 and MMP9 activity and suppression of E-cadherin in oesophageal squamous cell carcinoma (ESCC). STAT3 is one of the crucial transcription factors, responsible for regulating immune activation, angiogenesis, inflammatory response, programmed cell death, cellular differentiation, migration, and cellular proliferation . STAT3 participates in the signaling pathways for many cytokines in various cells and organs that are regulated by the suppressor of SOCS3 and the activation and function of STAT3 and SOCS3 in the lung during the acute inflammatory response are emerging. Cardiac-specific SOCS3 deletion enhanced multiple cardioprotective signaling pathways including extracellular signal-regulated kinase (ERK)-1/2, AKT and STAT3. As one member of the activator protein 2 (AP-2) TF family, TFAP2A is important for the regulation of gene expression during early development as well as carcinogenesis process. High ERBB2 expression may result either from gene amplification or from increased TFAP2A levels in breast tumours. However, the roles of four TFs, ELK1, ETV4, STAT3 and TFAP2A in COPD and AMI, and the four TFs interactions with hub genes, are still need further exploration.
However, there are several limitations in our study. First,our study is a microarray analysis that all the results based on gene expression value. The sample sizes were relatively small, and larger-sample, multicenter research is needed. Second, the DEGs screened in our study are associated with COPD and AMI, and external validation in vivo and in vitro experiments and with clinical cases is needed to consolidate our results. Additionally, it is necessary to perform functional studies to confirm the roles of the DEGs in COPD and AMI.