Background
Myocardial infarction (MI) is a global disease characterized by a high incidence and high mortality. More than 3 million people were newly diagnosed with ST-segment Elevation Myocardial Infarction (STEMI) and more than 4 million people were newly diagnosed with Non-ST-segment Elevation Myocardial Infarction (NSTEMI) worldwide. The incidence of myocardial infarction is relatively higher in developed countries and is rapidly increasing in developing counties, including China [
1]. Relevant epidemiological and basic science studies indicate that lifestyle factors and genetic factors jointly promote the progression of coronary atherosclerosis and the occurrence of myocardial infarction [
1‐
4]. An investigation involving over 15,000 MI patients was conducted by INTERHEART and indicated that most MI cases were caused by interactions among risk factors (i.e., smoking, dyslipidaemia, hypertension, abdominal obesity, diabetes, etc.) and susceptibility genes, resulting in coronary atherosclerosis [
4,
5]. Coronary heart disease is a complex genetic disease, and important inducing genes and susceptibility genes have been identified through many genetic studies using modern genetic technologies [
4].
Numerous studies have indicated that the gene expression levels in peripheral blood can reflect changes in and the progression of complex cardiovascular diseases, thus serving as a very significant biomarker for examining and diagnosing cardiovascular diseases [
6,
7]. Multiple studies have verified that gene module analyses can be used as a biomarker of disease progression or disease prognosis, and modular analyses of gene expression can be used to determine the prognosis of patients with breast cancer independent of breast cancer grading [
8]. The mRNA co-expression modules of AKT1, BRCA1, CCDC134, UBD and ZIC2 in peripheral blood can be used as biomarkers describing the progression of early-onset schizophrenia [
9]. The expression level of single genes at the mRNA level in peripheral blood can also be used as a genetic marker for the assessment of disease progression, and the overexpression of KIAA0101 at the mRNA level can be used as a predictor of the invasion and progression of liver cancer [
10], while the expression of KLKB1 at the mRNA level in monocytes in peripheral blood can be used as a molecular marker for the diagnosis and identification of chronic lymphocytic leukaemia patients and non-leukaemia patients [
11]. The expression level of CD36 at the mRNA level in monocytes in peripheral blood may mark the progression of coronary heart disease [
12], and the expression level of AdipoR2 at the mRNA level in peripheral blood is correlated with the progression of coronary atherosclerosis [
13].
A pathological study investigating myocardial infarction indicated that plaque rupture and subsequent thrombosis serve as the most important mechanisms of AMI [
14,
15]. In atherosclerosis, the imbalance in endothelial function can promote the occurrence of inflammatory activity [
16]. The endothelium can release adhesion molecules to absorb leucocytes and penetrate the intima, causing lipid deposition on the vessel wall and vascular inflammation. The inflammatory reaction can further promote phagocytosis of lipids by macrophages and, thus, the formation of foam cells. T-cells enter the intima and secrete cytokines that can enhance the inflammatory response and promote the migration and proliferation of smooth muscle cells in the intima [
17]. Furthermore, the inflammatory activity can weaken the fibrous cap of the atheromatous plaque and cause the occurrence of thrombosis, thus resulting in the occurrence of AMI [
17,
18].
The protein arginine methyltransferase (PRMT) family participates in many cellular responses, including the inflammatory response. The inflammatory response can cause various diseases related to inflammation or autoimmune diseases, including rheumatic arthritis, Alzheimer’s disease, systemic lupus erythaematosus, asthma, atherosclerosis, cancer, ischaemic heart disease, etc. [
19]. PRMT5 performs the function of regulating the on-off action of the inflammatory response [
19]. The results of an analysis of the differential gene expression profile in peripheral blood in myocardial infarction patients previously conducted by this research group indicate that compared to stable CAD patients, AMI patients had a differential low expression of the PRMT5 gene in their peripheral blood, and the expression level was 0.642 lower. Therefore, by expanding the sample size of the clinical data, this research group further investigated whether the PRMT5 gene, which is related to the inflammatory response, is correlated with AMI, assessed the value of the PRMT5 gene in the diagnosis of AMI and investigated whether the PRMT5 gene can be used as a biomarker in assessments of the risk of AMI.
Discussion
In this research, we discovered that compared to the stable CAD patients, the AMI patients had a low expression of the PRMR5 gene in their peripheral blood at both the mRNA and protein levels. Protein arginine methyltransferases (PRMTs) can catalyse the methylation of arginine and participate in many important cellular processes that are closely correlated to the occurrence, progression and invasion of tumours, T-lymphocyte activation and hepatic gluconeogenesis [
19]. PRMT5 performs many functions in the human body, can regulate the growth and transformation of cells [
26] and is correlated with various types of tumours. It is possible that the expression of the PRMT5 gene in pulmonary epithelial cells represents the first step in the promotion of the occurrence of lung adenocarcinoma [
27] and can promote proliferation in breast cancer cells [
28]. However, no research has investigated the correlation between PRMT5 and cardiovascular diseases. Four genes in the PRMT family, including CARM1, PRMT1, PRMT5, and PRMT6, are considered related to the inflammatory response [
19]. Inflammatory activity plays an important role in all phases of the progression of coronary heart disease, including thrombosis and development, and thrombosis is the cause of 80% of all sudden cardiac deaths [
29]. PRMT5 may play a role in regulating the on-off action of the inflammatory response in the endothelium [
19], which plays a role in regulating the inflammatory response in the endothelium by mediating the methylation of HOXA9 and regulating histone H4R3, which plays a role in gene silencing [
30,
31]. PRMT5 can also participate in the immune response and plays a key role in regulating the inflammatory response by mediating NF-kB [
19].
Currently, it is believed that during the progression from stable CAD to AMI, the inflammatory response plays an important role, and the PRMR5 gene serves as an important gene regulating response. Therefore, we reasonably speculate that the PRMR5 gene can promote the progression from stable CAD to AMI.
The results of this research indicate that not only was the PRMT5 gene differentially expressed but also that the levels of serum TC and LDL-C differed between the two groups based on the data. Through further analysis, we verified that the abnormal expression level of the PRMT5 gene is irrelevant to the levels of serum TC and LDL-C. Although it is generally believed that LDL can deposit at the subendothelium by integrating proteoglycan and be easily phagocytized by foam cells [
32] the progression of coronary atherosclerosis is further promoted [
33]. In addition, numerous studies have indicated that lipid-lowering therapy can reduce the risk of AMI among patients with coronary heart disease and increase their survival rate [
34,
35]. However, some studies have indicated that compared to stable CAD patients, AMI patients have relatively lower levels of serum TC and LDL-C. The highest degree of reduction in the levels of serum TC and LDL-C occurs during the period between 4 and 12 days after the occurrence of AMI, and the levels of serum TC and LDL-C are negatively correlated with the stability of atherosclerotic plaque, but the data from these groups in this research indicate that compared to the stable CAD patients, the AMI patients have higher levels of serum TC and LDL-C, which is inconsistent with previously reported results. However, the data of these groups in this research suggest that there is no correlation between the PRMT5 gene and the levels of serum TC and LDL-C, indicating that the PRMT5 gene does not promote coronary atherosclerosis and atheromatous plaques and, thus, causes AMI by influencing the levels of serum TC and LDL-C.
In this research, the results of the binary logistic regression analysis indicate that a low expression of the PRMT5 gene serves as an independent risk factor of the progression from stable CAD to AMI in patients and causes the risk of AMI to increase by 5.472 times. The increase in the serum TC and LDL-C levels is not a risk factor for progression from stable CAD to AMI in patients. However, the mechanism of the progression from atherosclerotic heart disease to AMI is not simple lipid accumulation and is realized through the vascular inflammatory response to a larger degree [
33]. Coronary heart disease is a disease caused by multiple responses, and inflammation plays an important role in the occurrence and progression of each phase and the final plaque rupture [
32]. By promoting the secretion of matrix metalloproteinase by plaques, which causes the degradation of extracellular matrix protein and weakens the fibrous cap, inflammation can further result in plaque rupture and thrombosis [
36] and promote the occurrence of myocardial infarction. Therefore, via its function of regulating the on-off action of inflammation, the PRMT5 gene may serve as an important susceptibility gene for the occurrence of AMI.
The results of this research also indicate that the relative expression level of the PRMT5 gene is correlated to the Gensini score, which indicates the severity of coronary artery lesions. Gensini scoring can be used to measure the severity of coronary artery lesions by adopting the method of quantitative coronary angiography in which different weights are adapted for different degrees of severity, and the result of the scoring is mainly correlated to the degree of coronary artery stenosis and scope of blood supply [
24], namely, the lower the relative expression level of the PRMT5 gene, the higher the Gensini score, and the more severe the coronary artery lesion. Therefore, based on this research, we speculate that the expression level of the PRMT5 gene is correlated with the severity of coronary artery lesions.
It has been verified through the analysis of the correlation between the expression level of the PRMT5 gene and cardiac troponin I (TnI) that the expression level of the PRMT5 gene is irrelevant to the level of cardiac troponin, but the level of cardiac troponin can reflect the scope of myocardial infarction; thus, the expression level of the PRMT5 gene may be irrelevant to the scope of myocardial infarction. Meanwhile, the expression level of the PRMT5 gene is irrelevant to the time interval of the occurrence of AMI. The time interval of occurrence refer to the interval from the onset of AMI in patients to the time of blood collection. Therefore, the variation in the scope of AMI is not accompanied by a decrease in the expression level of the PRMT5 gene, and the variation in the time interval of the occurrence of AMI is not accompanied by a decrease in the expression level of the PRMT5 gene. Therefore, we speculated that if low PRMT5 expression is a consequence of AMI, it should be correlated to the concentration of cardiac troponin I (TnI) and time interval of the occurrence of AMI. If low expression of PRMT5 leads to AMI, it should also have led to a change in the trend of cardiac troponin I (TnI) and time interval of the occurrence of AMI.
Therefore, based on the results of this research, we can speculate that the low expression of the PRMT5 gene may have an influence on coronary artery lesions by regulating the inflammatory response, thus promoting the occurrence of AMI.
Certainly, to clarify whether PCI influence level of the PRMT5 gene at the mRNA level or whether the low expression of the PRMT5 gene is a cause of AMI, it is still necessary to design forward-thinking studies.