Coronary artery disease is the most common cardiovascular disease. Studies on the positive and negative effects of miRNAs on the pathogenesis of the disease show that circulating miRNAs can be used as biomarkers in the diagnosis of coronary artery disease. Therefore, in our study, the role of miRNAs in the diagnosis of coronary artery disease and its relationship with the parameters in the clinical evaluation process were investigated.
miRNAs have gene regulatory effects [7]. In studies conducted in patients with myocardial infarction, serum levels of miR-1 and miR-133a are high [8, 9]. Heart-related studies of microRNAs have mostly focused on their effects on cardiac remodeling processes. It has been shown that miRNAs have significant potential in evaluating the early and late stages (early detection of a heart attack) of cardiac damage, regeneration, rhythm regulation, cardiac growth, and myocardial infarction [10–12]. miR-1, miR-133 and miR-208 have also been shown to be effective in many heart related conditions. These have been identified as "cardio-specific miRNAs" [5, 13, 14]. Therefore, we investigated human plasma samples that have not previously been studied in the presence of clinical data. We evaluated miRNA levels under ischemic conditions and obtained data that these miRNAs can be evaluated as markers in ischemic conditions in patients with coronary artery disease.
miR-21 is one of the miRNAs considered to be oncogenic due to its proliferative and anti-apoptotic effect in cancer cells [15, 16]. MiR-21 inhibition in cultured cardio myocytes was found to have a negative effect on cardio myocyte hypertrophy [17]. When MiR-21 is inhibited by antagomir approach, cardiac hypertrophy and fibrosis are reduced [18], as well as protective effects against heart damage caused by I/R [19]. This effect, which was initially useful in preventing cardiac damage, becomes harmful when the effects that lead to damage persist or recur. MiR-21 levels are high in unbalanced angina patients [20] and atherosclerosis model mice [21]. Patients with heart failure have high levels of miR-21, brain natriuretic peptide and miR-21 in serum samples collected from both the peripheral vein and coronary sinus [22]. In patients suffering from acute myocardial infarction, there is a strong correlation between miR-21 and cardiac markers such as cardiac troponin, CK and CK-MB [23].
In our study, a positive weak correlation was found between preoperative miR-21-5p and cardiac troponin values in the patient group. While there was no correlation between cardiac troponin and miR-21-5p values measured at postoperative hour 1, there was a negative and weak correlation between cardiac troponin measured at 1 hour and miR-21-5p measured at 24 hours. However, no correlation was found between CK-MB and miR-21-5p values at the 1st and 24th hours. Our patient group was not acute and was selected from individuals with a history of myocardial infarction. Therefore, we think that the miR-21 levels were lower in patients with coronary artery disease (p < 0.001). In addition, there was no significant difference between preoperative and postoperative miR-21-5p levels in patients with coronary artery disease (p < 0.05). These results were found to be different according to the literature data that miR-21 levels were higher in patients with coronary artery disease and heart failure compared [19–23]. This difference may be thought to occur because miR-21-5p levels correlate with cardiac markers. The diagnostic value of miR-21 in the patient group in our study could be considered as moderate. From this point of view, our results are consistent with the literature [24] and the nomination of miR-21 for diagnosis can be confirmed by repeated studies.
miR-199a-5p is localized in the introns of the dynamin genes and is expressed in cancer, brain, liver and cardiovascular system, particularly in cardio myocytes and endothelial cells [25, 26]. It is also associated with cancer and cardiovascular diseases [27, 28]. miR-199a-5p decreased in cardio myocytes exposed to hypoxia [27, 29[. High levels of miR-199a in circulating micro vesicles are associated with a reduced risk of cardiovascular events in patients with stable coronary artery disease [30]. In our study, miR-199a-5p levels were lower in patients with coronary artery disease than in the control group (p < 0.001). When miR-199a-5p changes were evaluated in the patient group before and after the operation, significant differences were found between the 1st and 24th hours (p < 0.044). The increase in the level of miR-199a 1 hour after the operation may be due to the saturation of the Hif-1alfa in the medium to achieve saturation and then to decrease its levels. MiR-199a-5p values measured in the patient group at 24th postoperative hour and cardiac troponin levels measured at 1 hour postoperatively were negatively moderately correlated. There was no significant relationship between miR-199a-5p and CK-MB values (p > 0.005). When we evaluate the obtained data, we think that changes in miR-199a-5p levels may be an important biomarker for coronary artery disease.
One of the miRNAs involved in cardiac hypertrophy is miR-199b-5p and plays an important role in the development of various organs such as the heart [31, 32]. miR-199b has been shown to activate the calcineurin/NFAT signaling pathway by targeting double-specific tyrosine phosphorylation-regulating kinase 1A [31] and improving heart function when miR-199b is inhibited [33]. It has been reported that miR-199b-5p regulates the nuclear factor kappa-B (NF-κB) signal pathway in the inflammatory response of the nervous system and suppresses neurodegenerative disease [34]. In another study, monocytes treated with lipopolysaccharide have been shown to have a significant decrease in miR-199b-5p levels and an increase in GSK3β expression and anti-inflammatory effect by activation of the NF-κB pathway [14]. In our study, miR-199b-5p levels were lower in patients with coronary artery disease compared to the control group (p < 0.001). Low miR-199b-5p levels result in the inability to inhibit NFκ-B protein and inflammation. Therefore, it can be said that it contributes to the etiopathogenesis of coronary artery disease. However, there was no significant difference between miR-199b-5p levels before and after surgery in patients with coronary artery disease (p > 0.05). There was no significant relationship between miR-199b-5p and cardiac troponin and CK-MB values for before and after operation in the patient group. According to ROC data, miR-199b-5p levels can be an important marker for coronary artery disease. We have seen in the literature that miR-199b-5p levels have not been studied in patients with coronary artery disease. To the best of our knowledge, this is the first study to investigate the correlation of miR-199b-5p levels with cardiac markers before and after bypass grafting in patients with coronary artery disease. Further studies are needed to evaluate miR-199b-5p levels in patients with coronary artery disease and to support our results.
miR-320a has been mostly studied in cancer and heart disease and also varies in heart disease, but has been studied in a limited number of patient groups [35, 36]. It suppresses cardio myocyte apoptosis of downregulation of miR-320a and protects against myocardial ischemia and reperfusion injury by targeting insulin-like growth factor 1 (IGF-1) [37]. In another study, it has been shown that downregulation of miR-320a suppresses cardio myocyte apoptosis and protects against myocardial ischemia and reperfusion damage by targeting insulin-like growth factor 1 (IGF-1) [38]. miR-320a is down-regulated in patients with myasthenia gravis [39]. In these patients, the expression of cyclooxygenase-2 (COX-2) is high, and over-expression of pro-inflammatory cytokines has been observed [40]. In our study, miR-320a levels were lower in patients with coronary artery disease compared to the control group (p < 0.004). There was no significant difference between the preoperative and postoperative miR-320a levels in patients (p > 0.05). There was a weak positive correlation between preoperative miR-320a levels and cardiac troponin levels in patients and there was no significant relationship between miR-320a and CK-MB. The first ROC analysis for miR-320a in patients with coronary artery disease was conducted in this study, and we believe it can be used to diagnose the disease, according to our data.
MiR-181a is highly expressed in the mammalian brain [41]. It plays an important role in various biological events, such as immune modulation and inflammation [42]. Inhibition of miR-181a has been found to increase neuronal loss due to ischemia and bcl-2 levels, which are anti-apoptotic protein [43] and upregulated in atherosclerotic vessels compared to normal vessels [44]. In the neurogenic hypertension model, miR-181a levels were low and renin mRNA levels were high [45]. In a study of unstable angina and acute myocardial infarction in circulation, MiR-181a levels were higher in the myocardial infarction group [14]. In our study, miR-181a levels were lower than the control group (p < 0.001). There was no change in miR-181a levels according to preoperative values after reperfusion with bypass graft (p > 0.05). There was a negative weak correlation between miR-181a-5p and cardiac troponin values after surgery in patients with coronary artery disease and weakly positive. There was a correlation between postoperative miR-181a-5p and CK-MB. The role of MiR-181a in cardiovascular diseases has not been described. As a result, miR-181a-5p has diagnostic potential in coronary artery disease. Therefore, we think that it can be considered as a biomarker for this disease if it is supported by new studies.