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American Journal of Cardiovascular Disease logoLink to American Journal of Cardiovascular Disease
. 2020 Jun 15;10(2):84–100.

Comparative study of gene expression profiles rooted in acute myocardial infarction and ischemic/reperfusion rat models

Jian-Fei Wang 1,*, Yan Huang 2,*, Sheng-Feng Lu 2, Hao Hong 3, Shun-Juan Xu 1, Jin-Song Xie 1, Zhou-Ye Wu 1, Yi Tang 4, Hou-Xi Xu 2, Shu-Ping Fu 2, Zhao-Qing Xi 1, Bing-Mei Zhu 2,3
PMCID: PMC7364282  PMID: 32685266

Abstract

Mining data in depth of genome-wide sequencing data generated from pathological target tissues under disease conditions is necessary for seeking novel functional genes, and developing more biological study directions for the field. Based on our previous published RNA-seq data generated from acute myocardial ischemia and ischemia-reperfusion in rat heart, we re-analysed these two data sets using bioinformatics tools. All these raw fastq files were extracted from Illumina BCL using the Illumina CASAVA program. Four groups were obtained: UD (genes up-regulated in MI but down-regulated in I/R injury), DU (genes down-regulated in MI but up-regulated in I/R injury), UU (genes both up-regulated in MI and I/R injury), and DD (genes both down-regulated in MI and I/R injury) groups. The results showed that 304 common genes in the UD group, 236 common genes in the DU group, 318 common genes in the UU group, and 159 common genes in the DD group detected by comparing data sets of the MI and the I/R injury. We then listed the top 30 DEGs for each group, and carried out GO and KEGG analyses for enrichment and pathway studies for those top expressed genes. Further analysis of INTERPRO Protein Domains and Features enriched by DEGs showed that 20% of the Domains enriched were related to c-type lectin, and 17% of these domains are related to neurotransmitter-gated ion-channel. 15% of PFAM Protein Domains were about Neurotransmitter-gated ion-channel. There were only 8 SMART Protein Domains DEGs enriched and 37.5% of which were concerned about leucine-rich. Collagen involvement in Reactome Pathways accounted for 22.7%. We found that only a few DEGs in these two disease conditions have been reported in the literatures, suggesting that there are many new genes would be considered in the future studies. These analyses would provide some information for seeking more novel targets of these two clinic diseases, acute myocardial ischemia and myocardial ischemia/reperfusion.

Keywords: Comparative study, gene expression profiles, myocardial infarction, myocardial ischemia-reperfusion, bioinformatics

Introduction

Acute myocardial infarction (MI) is a common critical disease with high morbidity and mortality worldwide [1]. MI results from the abrupt interruption of blood supply to a part of the heart, and lead to ischemia and even death of the affected cardiac tissue [2]. The treatment principle of acute myocardial infarction is to resume blood reperfusion on myocardial ischemia as soon as possible [3]. Primary percutaneous coronary intervention (PPCI), coronary artery bypass surgery (also known as coronary artery bypass graft, CABG) and drug thrombolytic are the three most effective therapies to recover ischemic myocardial blood flow [4-7]. In ischemic myocardial reperfusion, the status of myocardial ischemia might be corrected and cardiac functions are preserved. However, with blood reperfusion, part of the patients may suffer from lethal arrhythmias, cardiomyocyte death, and even death. It is difficult to accurately determine the boundaries between MI injury and I/R injury in clinic and the mechanism is not yet fully understood.

Expression profile analysis has been used to predict myocardial stress response to acute MI and myocardial I/R injury for many years [8,9]. In fact, molecular biology studies have confirmed 27 genetic variants that are concerned with the increased risk of MI [10]. In addition, recent progress in genotyping technology has made available newer and more powerful tools for the identification of susceptibility genes that in turn may provide new opportunities to evaluate the individual cardiovascular risk profile, detect novel disease pathways, and develop innovative therapeutic approaches. Some gene expression profile studies have made progress in dealing with acute MI and I/R injury, as well as the functional study of a single gene or few genes [11-14]. Thus, many research efforts continue to address the identification of acquired and inherited risk factors of these complex diseases. Many studies have hammered at I/R injury, ranging from basic research to clinical studies [15,16]. Furthermore, all these studies, especially for basic research, have come to some conclusions, but could not provide a full understanding of the molecular biology mechanism of MI and I/R injury. Therefore, it is significant to seek for new molecular biological evidence to distinguish the progress of MI and I/R injury and guide clinical practice.

In the present study, the gene expression profiles of MI (numbered GSE54132) and I/R (numbered GSE61840) in rats, which were generated by our previous studies, were compared, and uniquely and commonly up- or down-regulated genes under MI and I/R injury were screened [17,18]. Thus, four groups of differentially expressed genes (DEGs) were obtained: UD (genes up-regulated in MI but down-regulated in I/R injury), DU (genes down-regulated in MI but up-regulated in I/R injury), UU (genes both up-regulated in MI and I/R injury), and DD (genes both down-regulated in MI and I/R injury) groups. Database for Annotation, Visualization and Integrated Discovery (DAVID) tool was used in performing the Gene Ontology (GO) analysis and KEGG pathway analysis of each group of genes; and the Search Tool for Retrieval of Interacting Genes (STRING) database was performed to seek for protein-protein interaction (PPI) network constructions [19,20]. We preliminarily analyzed all the DEGs and items of the GO and KEGG pathway enrichment analysis, as well as PPI network constructions, and confirmed that these analysis tools are the directions of further research in the future.

Materials and methods

Data resources preprocessing and grouping

The gene expression profiles rooted in our previous studies and the raw data (GSE54132 and GSE61840) have been deposited onto the Gene Expression Omnibus database (GEO; http://www.ncbi.nlm.nih.gov/geo/) [17,18]. After ranking the up- and down-regulated genes in the MI-Control group and IR-SO (sham operation) group according to expression level from high to low, the four groups of DEGs (P<0.01 and Log2 fold change (FC) > |±1|) were compared. Following four groups of DEGs were obtained: UD, UU, DU and DD.

GO function analysis

The GO enrichment analysis of DEGs of the four groups was performed with DAVID, which provided a comprehensive set of functional annotation tools for investigators to understand the biological meaning behind the large list of genes [19]. GO terms were enriched with a threshold of P<0.01, according to the principle of hyper-geometric distribution.

Pathway enrichment analysis

Pathway analysis was used to identify related proteins within a pathway or build pathway de novo from the proteins of interest, which would help to study the differential expression of a gene in a disease or analyze any Omics dataset with a large number of proteins. It was used to carry out finding distinct cell processes (cellular processes), diseases or signaling pathways that are statistically associated with the selection of DEGs between two samples. In our study, the DAVID tool was also utilized for KEGG pathway analysis of the screened four groups of DEGs [19].

PPI network construction

In molecular biology, STRING 10.0, which is a tool for known and predicted protein-protein interactions based on a biological database and web resource, was performed to construct PPI networks in these four groups of DEGs [21]. ‘Nodes’ and ‘edges’ comprised the PPI network and a node represented a protein, while an edge revealed the interaction of pairwise proteins. In this study, String 10.0 was operated to search the PPI network construction for four groups of DEGs.

Statistical analysis

Data were presented as means ± standard deviation (SD). Statistics analysis was performed using SPSS 18.0; a one-way ANOVA analysis of variance followed by the Turkey HSD test is used for multiple group comparisons. P<0.05 was considered statistically significant.

Results

Data preprocessing

After comparing the 3,713 up-regulated genes in the MI with the 1,468 down-regulated genes in the I/R injury, 304 common genes (UD group) were obtained according to their relative expression levels. Furthermore, 236 common genes (DU group) were down-regulated in the MI and up-regulated in the I/R injury, 318 common genes (UU group) were both up-regulated in the MI and the I/R injury, and 159 common genes (DD group) were both down-regulated in the MI and the I/R injury. All four comparisons were listed and analyzed with Venn Diagrams as Figure 1. The grouping situation is shown in Table 1.

Figure 1.

Figure 1

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Venn diagrams and clustering analysis of RNA-seq results. (A-D) Venn diagrams were drawn based on the gene expression profiles of MI (numbered GSE54132) and I/R (numbered GSE61840) generated by our previous studies. Comparing the 3,713 up-regulated genes in myocardial infarction (MI) with the 1,468 down-regulated genes in ischemia/reperfusion (I/R), 304 common genes (UD group) were obtained. Furthermore, 236 common genes (DU group) were down-regulated in MI and up-regulated in I/R, 318 common genes (UU group) were both up-regulated in MI and I/R, and 159 common genes (DD group) were both down-regulated in MI and I/R. Red circles indicate the numbers of genes up- (B, C) or down-regulated (A, D) in I/R group; green circles represent the numbers of up- (A, B) or down-regulated (C, D) genes in MI group.

Table 1.

Differentially expressed genes (DEGs) across four groups

Category Group DEGs
MI-Up vs. IR-Down UD 304
MI-Up vs. IR-Up UU 318
MI-Down vs. IR-Up DU 236
MI-Down vs. IR-Down DD 159
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Note: Comparing the 3,713 up-regulated genes in myocardial infarction (MI) with the 1,468 down-regulated genes in ischemia/reperfusion (I/R), 304 common genes (UD group) were obtained. Furthermore, 236 common genes (DU group) were down-regulated in MI and up-regulated in I/R, 318 common genes (UU group) were both up-regulated in MI and I/R, and 159 common genes (DD group) were both down-regulated in MI and I/R.

The top 30 DEGs from the four groups analyzed

The top 30 DEGs with the highest fold changes in the UD group were listed in Table S1. We found that some genes listed in this top 30 DEGs were previously reported, such as Cpz, Scn9a, Kcne1, Tnfrsf12a, Has1, Camp, Micb, Cyr61 and Hmox1 with MI or I/R injury [22-31]. In the top 30 DEGs in the DU group (Table S2), only Cyp1a1, Kcnma1, Cd69 and Il1a have been reported [32-35]. None of the rest of the 28 genes was reported in relation to MI or I/R injury. In addition, only few studies stated the functions of Itga4, Msr1 and Cybb in MI or I/R injury in the top 30 DEGs in the UU group (Table S3) [36-38]. In the top 30 DEGs in the DD group (Table S4), Treml1, Alox15, vnn3, Gata1 and Pbx4 have been reported in relation to MI or I/R injury with extreme limitations [39-43]. All research situations were shown in Table 2.

Table 2.

Research situations of the top 30 differentially expressed genes of the four groups analyzed

Items UD UU DU DD
Reported to be related to MI or I/R Cpz, Scn9a, Kcne1, Tnfrsf12a, Has1, Camp, Micb, Cyr61, Hmox1 Itga4, Msr1, Cybb Cyp1a1, Kcnma1, Cd69, Il1a Treml1, Alox15, vnn3, Gata1, Pbx4
Not reported to be related to MI & I/R injury Cldn23, Gsc, Cldn4, Ankrd2, Prss3, Tbx15, Ngp, Ntf4, Gbx2, Cd177, Scn3a, Hunk, P2rx2, Olfm2, Msln, P4ha3, Sulf2, Rhbdl2, UDUpd1, Kcnc1, Areg, Sh2d1a Glra2, Gpr65, Klra5, Gpr34, Ipcef1, Tm4sf4, LOC500948, Trpv6, Kynu, Bank1, Galnt5, Dixdc1, Rnase11, Ndst3, Hs6st2, Mctp2, Inhba, Slc27a6, Clec4a2, Rims2, Zdhhc23, C1ql3, Gpr160, Scel, Trat1, Lilra5, Ly49si1 Tuba3a, Klre1, Nxph1, Btla, Crygf, Dmrta1, Sh2d1a, Abcg3l4, Clec12b, RGD1311251, Cntn1, Agr2, Hapln1, Slc13a5, Glb1l3, MGC105567, Il24, Dppa3, Pde1c, Cpvl, Rsph1, Zfp68, Klrk1, Jph3, Tectb, Hpgds Pnliprp1, Sgpp2, Enpp6, Hoxb9, Vpreb1, RGD1308775, Hist2h4, Spdef, Klk1c9, Trim43a, Atp6v1g2, Vdac3, Mybphl, Add2, Car1, Adam11, Vpreb2, Dlk1, Guca1b, Cbln1, Oc90, Akr1c1, Akap3, Tecta, Atp6ap1l
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Note: UD: genes up-regulated in myocardial infarction (MI) but down-regulated in ischemia/reperfusion (I/R); DU: genes down-regulated in MI but up-regulated in I/R; UU: genes both up-regulated in MI and I/R; DD: genes both down-regulated in MI and I/R. Only 9 genes in UD group have been reported related to MI and I/R injury before, and only 3 in UU group, 4 in DU group, and 5 in DD group. But a total of nearly 100 common genes in relating to MI or I/R have not been reported in the four groups.

GO enrichment analysis

GO enrichment analysis of DEGs of the four groups were performed with the DAVID tool (Table 3). In the UD group, there were a total of 22 items on Molecular Function, 22 items on Cellular Component and 106 items on Biological Process. In the UU group, there were 18 items on Molecular Function, 15 items on Cellular Component and 49 items on Biological Process. In the DU group, there were 10 items on Molecular Function, five items on Cellular Component and 32 items on Biological Process. In the DD group, there were eight items on Molecular Function, six items on Cellular Component and 31 items on Biological Process. The comparison of the GO enrichment analysis data of the four groups revealed that 21 GO ids were in common in gene ontological domains among different groups. In the UD group, five GO ids were in common with other groups in the Molecular Function domain, seven GO ids were in common with other groups in the Cellular Component domain, and six GO ids were in common with other groups in the Biological Process domain. All items of the GO enrichment analyses of these four groups were shown in Table 4. The GO enrichment analysis items of top 30 differentially expressed genes of four groups were shown in Figure 2.

Table 3.

Items of the Gene Ontology enrichment analysis of the four groups

Items UD UU DU DD Total
Molecular Function (MF) 22 18 10 8 58
Cellular Component (CC) 22 15 5 6 48
Biological Process (BP) 106 49 32 31 218
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Note: UD: genes up-regulated in myocardial infarction (MI) but down-regulated in ischemia/reperfusion (I/R); DU: genes down-regulated in MI but up-regulated in I/R; UU: genes both up-regulated in MI and I/R; DD: genes both down-regulated in MI and I/R. The Gene Ontology (GO) enrichment analysis showed that most genes in each group concentrated in Biological Process.

Table 4.

Items of the Gene Ontology (GO) enrichment analysis of the four groups

Common GO id and Description Groups and Categories Common GO id and Description Groups and Categories
GO:0008083~growth factor activity UD-Molecular Function, UU-Molecular Function GO:0072562~blood microparticle UD-Cellular Component, UU-Cellular Component
GO:0005125~cytokine activity UD-Molecular Function, UU-Molecular Function, DU-Molecular Function GO:0030246~carbohydrate binding DU-Molecular Function, UU-Molecular Function
GO:0005509~calciumion binding UD-Molecular Function, UU-Molecular Function GO:0005249~voltage-gated potassium channel activity DU-Molecular Function, UU-Molecular Function
GO:0005102~receptor binding UD-Molecular Function, UU-Molecular Function GO:0009897~external side of plasma membrane DU-Cellular Component, UU-Cellular Component
GO:0020037~heme binding UD-Molecular Function, DD-Molecular Function GO:0070374~positive regulation of ERK1 and ERK2 cascade UD-Biological Process, DD-Biological Process
GO:0005615~extracellular space UD-Cellular Component, DD-Cellular Component, UU-Cellular Component GO:0044344~cellular response to fibroblast growth factor stimulus UD-Biological Process, DD-Biological Process
GO:0005576~extracellular region UD-Cellular Component, DD-Cellular Component GO:0043627~response to estrogen UD-Biological Process, DD-Biological Process
GO:0005578~proteinaceous extracellular matrix UD-Cellular Component, UU-Cellular Component GO:0042593~glucose homeostasis UD-Biological Process, DD-Biological Process
GO:0016324~apical plasma membrane UD-Cellular Component, UU-Cellular Component GO:0007010~cytoskeleton organization UD-Biological Process, DD-Biological Process
GO:0005887~integral component of plasma membrane UD-Cellular Component, DU-Cellular Component, UU-Cellular Component GO:0051591~response to cAMP UD-Biological Process, DD-Biological Process
GO:0009986~cell surface UD-Cellular Component, UU-Cellular Component
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Note: UD: genes up-regulated in myocardial infarction (MI) but down-regulated in ischemia/reperfusion (I/R); DU: genes down-regulated in MI but up-regulated in I/R; UU: genes both up-regulated in MI and I/R; DD: genes both down-regulated in MI and I/R. There are totally 21 Common Gene Ontology IDs and Descriptions which concerned different groups.

Figure 2.

Figure 2

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Gene Ontology enrichment analyses of DEGs of the four groups were performed with the DAVID. A-D. Correspond to UD, UU, DU, and DD group separately. (*P<0.05) UD: genes up-regulated in myocardial infarction (MI) but down-regulated in ischemia/reperfusion (I/R); DU: genes down-regulated in MI but up-regulated in I/R; UU: genes both up-regulated in MI and I/R; DD: genes both down-regulated in MI and I/R.

KEGG pathway analysis

Furthermore, the DAVID tool was also utilized for the KEGG pathway analysis of the four groups of screened DEGs. In the UD group, 44 KEGG pathways were enriched by DEGs with the smallest P-value (1.37E-04) and FDR (0.17). The pathway with the biggest fold enrichment (6.92, rno04974: protein digestion and absorption) was associated with the metabolism of protein. The complement and coagulation cascades pathway (rno04610, P=0.002247062) is concerned about the complement system and coagulation system. The 42 KEGG pathways were enriched by DEGs in the UU group, in which the term with the smallest P-value (4.73E-05) and FDR (0.058523675) was neuroactive ligand-receptor interaction (rno04080). In the DU group, 29 KEGG pathways were enriched by DEGs, in which renin secretion pathway (rno04924) had the smallest P-value (0.005544226) and FDR (6.416363241). In the DD group, 31 KEGG pathways were enriched by DEGs, in which the term with the smallest P-value (0.002628711) and FDR (2.949112652) was the cAMP signaling pathway (rno04024). All pathways added up to 146, which are listed in Table 5.

Table 5.

Items of the KEGG pathway analysis of the four groups

Items UD UU DU DD
Amount of KEGG pathways 44 42 29 31
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Note: UD: genes up-regulated in myocardial infarction (MI) but down-regulated in ischemia/reperfusion (I/R); DU: genes down-regulated in MI but up-regulated in I/R; UU: genes both up-regulated in MI and I/R; DD: genes both down-regulated in MI and I/R.

When deeply looking into all the KEGG pathway analysis results, 30 (20.5%) common KEGG pathway terms among the four groups were picked out and shown in Table 6. Neuroactive ligand-receptor interaction (rno04080) was the common pathway among the four groups. Furthermore, 17 common pathways were concerned about the UD or DU group (56.7%), 21 common pathways were concerned about the UU group (70%), and 15 common pathways were concerned about group DD (50%). The KEGG pathways analysis items of top 30 differentially expressed genes of four groups were shown in Figure 3.

Table 6.

Distribution of the common KEGG pathway analysis in the four groups

Common KEGG pathway term Groups Common KEGG pathway term Groups
rno04080:Neuroactive ligand-receptor interaction UD, UU, DU, DD rno04630:Jak-STAT signaling pathway UD, UU, DU
rno04610:Complement and coagulation cascades UD, UU rno04512:ECM-receptor interaction UD, UU, DU
rno04060:Cytokine-cytokine receptor interaction UD, UU, DU rno05032:Morphine addiction UU, DU
rno04640:Hematopoietic cell lineage UU, DU, DD rno00250:Alanine, aspartate and glutamate metabolism UU, DD
rno03320:PPAR signaling pathway UD, UU rno04915:Estrogen signaling pathway UD, UU
rno00590:Arachidonic acid metabolism UU, DD rno00260:Glycine, serine and threonine metabolism UU, DD
rno04725:Cholinergic synapse UD, UU rno04510:Focal adhesion UD, DD
rno04750:Inflammatory mediator regulation of TRP channels UD, UU rno04020:Calcium signaling pathway UD, DD
rno04514:Cell adhesion molecules (CAMs) UD, UU, DU rno04916:Melanogenesis UD, DU
rno04978:Mineral absorption UD, UU rno04024:cAMP signaling pathway UD, DU, DD
rno04151:PI3K-Akt signaling pathway UD, UU, DU rno04540:Gap junction DU, DD
rno04730:Long-term depression UU, DU rno04022:cGMP-PKG signaling pathway DU, DD
rno04014:Ras signaling pathway UU, DD rno04975:Fat digestion and absorption DU, DD
rno05133:Pertussis UU, DD rno04145:Phagosome DU, DD
rno04970:Salivary secretion UD, UU, DU rno04923:Regulation of lipolysis in adipocytes DU, DD
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Note: UD: genes up-regulated in myocardial infarction (MI) but down-regulated in ischemia/reperfusion (I/R); DU: genes down-regulated in MI but up-regulated in I/R; UU: genes both up-regulated in MI and I/R; DD: genes both down-regulated in MI and I/R. There are totally 30 common KEGG pathways analysis which concerned two or more groups.

Figure 3.

Figure 3

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Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of four groups of DEGs. A-D. Correspond to UD, UU, DU, and DD group separately. (*P<0.05) UD: genes up-regulated in myocardial infarction (MI) but down-regulated in ischemia/reperfusion (I/R); DU: genes down-regulated in MI but up-regulated in I/R; UU: genes both up-regulated in MI and I/R; DD: genes both down-regulated in MI and I/R.

PPI network construction

After operating String 11.0 (https://string-db.org/), the Protein-protein interaction network of the four groups DEGs was constructed. In the UD group, the PPI network contained 95 nodes, 104 edges and 53 expected edges, with 2.19 average node degrees (PPI enrichment P-value: 3.04e-10). The PPI network of DEGs in the UU group contained 192 nodes, 441 edges and 316 expected edges, with 4.59 average node degrees (PPI enrichment P-value: 2.08e-11). In the DU group, the PPI network contained 181 nodes, 309 edges and 225 expected edges, with 3.41 average node degrees (PPI enrichment P-value: 7.49e-08). Analogously, the PPI network of DEGs in the DD group contained 159 nodes, 278 edges and 175 expected edges, with 3.50 average node degrees (PPI enrichment P-value: 3.84e-13) (Table 7). INTERPRO Protein Domains and Features showed 35 domains significantly enriched in the four DEGs groups (Table 7). All the domains mainly included Voltage-dependent channel domain superfamily, Toll/interleukin-1 receptor homology (TIR) domain superfamily, Neurotransmitter-gated ion-channel ligand-binding domain superfamily, Neurotransmitter-gated ion-channel transmembrane domain superfamily, Neurotransmitter-gated ion-channel ligand-binding domain, Toll/interleukin-1 receptor homology (TIR) domain, Immunoglobulin-like domain superfamily, Natural killer cell receptor-like, and C-type lectin-like domain. All PPI network construction pictures were shown in Figure 4.

Table 7.

Items of the protein-protein interaction (PPI) network constructions of the four groups

Items Number of nodes Number of edges Average node degree Clustering coefficient Expected number of edges PPI enrichment P-value
UD 95 104 2.19 0.672 53 3.04E-10
UU 192 441 4.59 0.382 316 2.08E-11
DU 181 309 3.41 0.577 225 7.49E-08
DD 159 278 3.5 0.568 175 3.84E-13
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Note: UD: genes up-regulated in myocardial infarction (MI) but down-regulated in ischemia/reperfusion (I/R); DU: genes down-regulated in MI but up-regulated in I/R; UU: genes both up-regulated in MI and I/R; DD: genes both down-regulated in MI and I/R.

Figure 4.

Figure 4

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Protein-protein interaction (PPI) network construction was connected with the Search Tool for Retrieval of Interacting Genes (STRING) database. A-D. Correspond to UD, UU, DU, and DD group separately. (*P<0.05) UD: genes up-regulated in myocardial infarction (MI) but down-regulated in ischemia/reperfusion (I/R); DU: genes down-regulated in MI but up-regulated in I/R; UU: genes both up-regulated in MI and I/R; DD: genes both down-regulated in MI and I/R.

Discussion

MI and I/R injury are both common diseases in clinic and have heavily threatened patients with cardiovascular disease. In 2013, more than 8.6 million people suffered from MI worldwide [44]. Although there are numerous studies on MI and I/R injury, the molecular mechanisms of MI and I/R injury are not fully understood. Preliminary genetic sequencing shows that acute MI or I/R can all lead to the increase in gene expression or cut [45,46]. However; studies in this field are far from adequacy.

In order to further investigate genes related to MI and I/R injury and their relationship with these two diseases, we studied four different groups of genes in rat models, and found that most DEGs in the four groups had not been studied in relation to MI or I/R injury.

In the top 30 genes in the UD group, 10 genes (Cpz, Scn9a, Kcne1, Tnfrsf12a, Has1, Camp, Micb, Cyr61, Hmox1 and Sh2d1a) have been reported to be concerned about MI or I/R injury. Hmox1 and Tnfrsf12a both have been proven to have a direct relationship between MI and I/R. Hmox1, which belongs to the hemeoxygenase family, was considerably up-regulated with 2.9351 of Log2 FC by MI and down-regulated with -2.22313 of Log2 FC. Causey et al. has reported that Tnfrsf12a, as a member of TNF family, play a crucial role in apoptosis, cell death and angiogenesis, as well as cardiac remodeling and vascular development [47]. Cldn23 and Cldn4 are all encoded members of the claudin family. However, studies about two genes were all the association of these with tumors, whereas no report was found on the correlation with acute MI or I/R injury [48]. Cyr61, which was outstandingly up-regulated with 1.168 of Log2 FC by MI and down-regulated with -2.22702 of Log2 FC, is a member of the growth factor-inducible immediate early genes and can modulate inflammation. Bonda TA, et al. found that the expression of Cyr61 protein was only slightly attenuated and had no influence in IL-6 KO mice after MI, but Cyr61 distribution was significantly changed when blockading the AT1 receptor [27]. It is noteworthy that the biological effects of these genes, being up-regulated genes in MI with the down-regulated genes in IR such as Gsc, Cpz, Ankrd2, Prss3, and Tbx15 have not been fully researched. All these findings by this comparative study may shed light on the MI and I/R research filed.

In the top 30 genes in the DU group, five genes (Cyp1a1, Abcg3l4, Kcnma1, Cd69 and Il1a) had been proven to be related to MI or I/R injury. Kcnma1 (potassium large conductance calcium-activated channel, subfamily M, alpha member 1, MaxiK) is a protein coding gene. In our study, the expression of Kcnma1 was outstandingly down-regulated with 1.727 of Log2 FC on MI and up-regulated with -2.22702 of Log2 FC on IR, which signified that the damaged biological functions of MaxiK may be recovered with the reperfusion of blood, which was also confirmed by many other researches [33]. Fretwell L et al. found that BK (Ca) channels participated in adenosine A1 receptor-induced pharmacological post-conditioning in a cell model system by reducing H/R-induced LDH release [49]. Tomás M et al. discovered that the Ca2+-dependent potassium channel could control human blood pressure and impact cardiovascular disease, and the genetic variation in the Kcnma1 potassium channel alpha subunit could severely increase systolic hypertension and general hypertension [50].

In the top 30 genes in the UU group, only three genes (Itga4, Msr1 and Cybb) have been studied in relation to acute MI or (and) I/R injury. Itga4 encodes a member of the integrin alpha chain family of proteins, which come into play in cell motility and migration. Wingerd KL et al. found that Itga4 plays an important role in axons development and innervations, which was expressed on developing axons in vivo [51]. Msr1 can encode class A macrophage scavenger receptors. Tsujita K et al. found that the risk of cardiac rupture with MI was increased when targeted knocking out the class A macrophage scavenger receptor [52]. Shantsila E et al. described that the expression level of Msr1 on Mon1 was related to tissue type plasminogen activator levels, and thus, inferred CXCR4 positive and angiogenic monocytes in MI [53]. Cybb has been proposed as a primary component of the microbicidal oxidase system of phagocytes. Almeida SA et al. found that the mechanism of improving functional cardiac parameters subjected to MI of exercise training might be concerned with the decreasing expression of both Cybb and AT1 receptor [37]. Xu J et al. reported that the increased protein expression of Cybb and transforming growth factor β1 resulted in ventricular dilatation, as well as dysfunction, interstitial fibrosis and myocardial hypertrophy, which was caused by MI.

In the top 30 genes in the DD group, five genes (Treml1, Alox15, vnn3, Gata1 and Pbx4) were detected. Treml1 and Alox15 were studied in relation to MI or I/R injury. Treml1 is a triggering receptor expressed on myeloid cells like 1. Recent researches suggested that the soluble triggering receptor could facilitate atherothrombosis, which helps understand atherothrombosis-associated acute coronary syndrome [42]. Recent studies have shown that Alox15 is involved in inflammation and have been implicated in atherosclerosis, and then related to stroke, MI, and coronary artery disease (CAD) [41].

At the same time, we found many issues on the GO enrichment analysis of DEGs in the four groups worthy of further study. First, there were a total of 58 GO items on Molecular Function, 48 GO items on Cellular Component and 218 GO items on Biological Process. When MI and I/R injury occurred, myocardial cells, including the subsidiary of the neurovascular, produced a series of molecular biological changes; and these changes would be reflected in the results of the GO enrichment analysis [54]. Second, some GO terms were commonly shared in different groups, and a total of 21 common GO terms were found. Some common GO terms, such as growth factor activity (GO:0008083), cytokine activity (GO:0005125) and cellular response to fibroblast growth factor stimulus (GO:0044344), played important roles in inflammation and cell apoptosis [55,56].

Similarly, a total of 148 KEGG pathways were found from the DEGs of the four groups. Many pathways such as the TNF signaling pathway (rno04668), p53 signaling pathway (rno04115), and leukocyte transendothelial migration (rno04670) had been proven to be of significance in the molecular mechanisms of MI or I/R injury [57,58]. However, the overwhelming majority of these pathways had not been researched in relation to MI or I/R injury. It is worth noting that there were 30 common pathways of many different groups. Neuroactive ligand-receptor interaction (rno04080) was a common pathway in the four groups, but no studies with MI or I/R injury have been reported. With pathway analysis, we can find distinct cell processes, diseases or signaling pathways that are statistically associated with selection of deferentially expressed genes between two samples [59]. Common pathways in different groups meant different physiological and pathological process share common molecular mechanisms. Meanwhile, the results of the PPI network constructions of the four groups revealed that a total of 159 nodes, 278 edges, and 175 expected edges. However, very limited studies have been conducted on these PPI networks so far.

Conclusion

In conclusion, by comparing the gene expression profiles of MI and I/R injury models, we obtained four groups of differentially expressed genes, and GO function and KEGG pathway enrichment analyses were carried out from the four groups of DEGs. All these results provide vast areas for the subsequent research in finding mechanism of MI and I/R injury and developing new therapeutic targets.

Acknowledgements

This study was supported by the National Key R&D Program of China (No. 2019YFC1709003) the National Natural Science Foundation of China (Grant No. 81870224 & 81574063), and the national basic research program of China (973 program, Grant No. 2012CB518501).

Disclosure of conflict of interest

None.

Supporting Information

ajcd0010-0084-f5.pdf (207.4KB, pdf)

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