Apelin-12

BACKGROUND: The aim of this study was to determine whether spironolactone therapy has an effect on serum apelin-12 levels in heart failure with reduced ejection fraction (HFrEF) patients. METHODS: Eighty outpatients previously diagnosed with HFrEF were enrolled in the current study. Included patients were taking only standard heart failure therapy (ST) (angiotensin converting enzyme or angiotensin receptor blocker, beta-blockers, loop diuretics and anticoagulant or antiagregan agents) without a mineralocorticoid receptor antagonists (MRA) because of its side effects, and were designated the non-MRA group; those patients taking 25 mg/daily spironolactone in addition to the ST were deemed the MRA group. Patient blood samples were collected to measure serum apelin-12 levels. RESULTS: After adjustment for all clinical and demographic factors, plasma apelin-12 levels were significantly higher and NT pro-BNP levels were significantly lower in the MRA group compared to the non-MRA group (p < 0.001, p < 0.001; respectively). In multiple linear regression analyses, there was no association between baseline apelin-12 level and clinical parameters. MRA using initial apelin-12 levels were lower and NT pro-BNP levels were higher in patients with stricken event than in event-free patients (p = 0.042, p < 0.001, and p < 0.001; respectively). CONCLUSIONS: Blocking the aldosterone receptors by spironolactone, in addition to maximal standard therapy, may increase serum apelin-12 levels among patients with HFrEF.

BACKGROUND: To analyze the expression levels of plasma dimethylglycine (DMG), human maternally expressed gene 3 (MEG3), and Apelin-12 in patients with acute myocardial infarction (AMI) and explore their clinical significance. METHODS: One hundred and ten patients with suspected AMI (chest pain duration <6 h) who were admitted to our hospital between December 2018 and June 2020 were included. Plasma DMG, MEG3, and Apelin-12 levels were measured at the time of admission. The levels of plasma DMG, MEG3, and Apelin-12, as well as the general data and admission baseline data of these patients were then compared with those of non-AMI patients. The receiver operating characteristic (ROC) curve was used to analyze the clinical value of plasma DMG, MEG3, and Apelin-12 levels for the early diagnosis of AMI. RESULTS: Among the 110 patients with chest pain suspected of AMI, 34 were clinically diagnosed with AMI, and 76 were non-AMI patients. The proportion of males, smoking, history of myocardial infarction, and congestive heart failure in the AMI group were higher than those of the non-AMI group. The proportions of systolic blood pressure (SBP), ST-segment elevation, and electrocardiogram (ECG) dynamic changes on admission were also higher in the AMI group compared to those of the non-AMI group (P<0.05). The plasma DMG, MEG3, and Apelin-12 levels of patients in the AMI group on admission were higher than those of the non-AMI group (P<0.05); all have diagnostic value for AMI upon admission. The area under the curve (AUC) of MEG3 was higher than that of both DMG and Apelin-12, however the difference was not statistically significant (Z=1.378, 0.934, P=0.168, 0.350). Using 0.015 as the cut-off value for MEG3-messenger ribonucleic acid (mRNA), the sensitivity and specificity for diagnosing AMI were 85.29% and 81.58%, respectively. CONCLUSIONS: Our results showed that the plasma levels of DMG, MEG3, and Apelin-12 in patients with AMI were high, and thus, they can be used as biomarkers for the early diagnosis of AMI. Among them, MEG3 was the most effective in early diagnosing AMI.

BACKGROUND: Apelin-12 and estimated glomerular filtration rate (eGFR) are considered prognostic factors for ST-segment elevation myocardial infarction (STEMI). However, little is known about whether the combined use of these two biomarkers could enhance the prognostic value. This study aimed to investigate the utility of combining apelin-12 and eGFR for STEMI. METHODS: Patients were divided into four groups based on median apelin-12 level and eGFR level: A: low apelin-12, low eGFR; B: low apelin-12, high eGFR; C: high apelin-12, low eGFR; and D: high apelin-12, high eGFR. The Cox regression was used to identify prognostic factors. The Kaplan-Meier and the receiver operating characteristic (ROC) curves were generated to evaluate the prognostic value of apelin-12 combined with eGFR in patients with STEMI. RESULTS: Among 460 patients, 118 (25.7%) experienced major adverse cardiac events (MACEs) during the entire follow-up of 30 months. The Kaplan-Meier curve analysis revealed that group D had the best prognosis compared with the other three groups. The combination of apelin-12 and eGFR (area under the ROC curve (AUC), 0.699) enhanced the predictive value for MACE compared with either apelin-12 (AUC, 0.617) or eGFR (AUC, 0.596) alone. There was a negative association between apelin-12 and eGFR (r = -0.32, p < 0.001), while no association was observed between the Gensini score and apelin-12 or eGFR. CONCLUSIONS: This study suggests that both low apelin-12 (<0.76 ng/ml) and low eGFR (<94.06 mL/min/1.73 m2) are associated with poor prognosis in STEMI, indicating that the combination of apelin-12 and eGFR could enhance the prognostic value of patients with STEMI.

BACKGROUND: Acute myocardial infarction is characterised by an imbalance in the supply and demand of oxygen in the heart. It requires urgent reperfusion, and poor outcomes are attributed to myocardial ischaemia-reperfusion injury. We aimed to evaluate the association between apelin-12 levels and creatine kinase-MB activity in predicting the effectiveness of reperfusion therapy in ST-segment elevation myocardial infarction (STEMI) patients. METHODS: In this study we included 72 patients with the following criteria: chest pain suggestive of myocardial ischaemia for at least 30 minutes, an electrocardiogram with ST-segment elevation (measured at the J-point) ≥ 2 mm in leads V2-V3 and/or ≥ 1 mm in the other leads, rise of specific biomarkers such as cardiac troponin and the MB fraction of creatine kinase (CK-MB), and those who underwent reperfusion therapy. Blood samples for the measurement of apelin-12 and creatine kinase-MB were collected 12 hours after the reperfusion therapy. RESULTS: In patients with thrombolysis in myocardial infarction (TIMI) flow grade ≤ 2, the median of the apelin-12 level was 1.80 ng/ml (0.46-9.20), and with TIMI flow 3, it was 5.76 ng/ml (1.14-15.2). Variability was observed in the apelin values (Mann-Whitney test) based on TIMI flow grade (p < 0.001), while no variability was observed for creatine kinase-MB (p < 0.18). The degree of association between apelin-12 and creatine kinase-MB levels was analysed with Pearson's correlation, enabling us to determine patients with successful reperfusion (determined as TIMI flow 3) (p < 0.004), and those with unsuccessful reperfusion (with TIMI flow ≤ 2) (p = 0.86). CONCLUSION: In STEMI patients undergoing reperfusion therapy, Apelin-12 level was associated with creatine kinase-MB activity according to the success of the reperfusion.

Chemically modified peptide apelin-12 ([MeArg1, NLe10]-apelin12, peptide M) is able to reduce reactive oxygen species (ROS) formation, cell death, and metabolic and ionic homeostasis disorders in experimental myocardial ischemia-reperfusion injury. These beneficial effects indicate the therapeutic potential of this compound in cardiovascular diseases. The goals of this work were to optimize the synthesis of peptide M, and to study its proteolytic stability and effect on the heart function of rabbits with doxorubicin (Dox) cardiomyopathy. We have developed a rational method of solid-phase synthesis of peptide M using the Fmoc methodology in combination with the temporary protection of the guanidine function of arginine residues by protonation (salt formation) during the formation of the amide bond. It avoids the formation of by-products, and simplifies the post-synthetic procedures, providing an increase in the yield of the final product of higher purity. Comparative evaluation of the proteolytic stability of peptide M and apelin-12 in human blood plasma was carried out using 1H NMR spectroscopy. It was shown that the half-life of peptide M in plasma is approximately three times longer than that of apelin-12. Intravenous infusion of increasing doses of peptide M caused a gradual increase in left ventricular (LV) fractional shortening and ejection fraction in rabbits after 8 weeks of Dox administration (2 mg/kg weekly). The effect of the modified peptide on LV systolic dysfunction was significantly more pronounced than the effect of apelin-12, which suggests the promise of using this pharmacological agonist of the APJ receptor in patients with heart failure.

The use of pharmacological agents to trigger preconditioning mechanisms may improve the prevention and treatment of coronary heart disease. The aim of this study was to evaluate the ability of a structural analog of apelin-12 ((NαMe)Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-OH, metilin) to reproduce the effect of ischemic preconditioning (IP) of rat hearts in vivo. Control rats were exposed to 40-min occlusion of the left descending coronary artery (LDCA) followed by 60-min restoration of coronary blood flow (reperfusion). IP was modeled by three cycles of 5-min occlusion/5-min reperfusion of the LDCA before prolonged regional myocardial ischemia and reperfusion. Metilin (5 mg/kg) was administered to rats intravenously by bolus injection 30 min before LDCA occlusion. IP or metilin had a significant impact on the studied parameters. The size of necrotic damage to the left ventricle, expressed as the percentage ratio of myocardial infarction/myocardial area at risk (MI/AAR, %), at the end of reperfusion was 26.9±2.0% and 29.3±2.6%, respectively, compared with 43.8±1.2% in the control (p < 0.01). The activity of creatine kinase-MB (CK-MB) in blood plasma decreased to 1026.1±93.9 IU/ml and 1195.2±142.0 IU/ml, respectively, compared with 1986.3±193.7 IU/ml in the control (p < 0.02). Administration of metilin, as well as IP, increased the reduced content of ATP, total adenine nucleotide pool (ΣAN) and phosphocreatine (PCr) in the AAR at the end of reperfusion compared to the control (p < 0.05-0.01). In the metilin group, the content of total creatine (ΣCr) in AAR was higher than in the control (p < 0.05). Intravenous administration of 5 mg/kg 5-hydroxydecanoate (5HD), an inhibitor of mitochondrial ATP-dependent K+ channels (mitoKATP), abolished the preconditioning effect of metilin, and increased the MI/AAR, %, and plasma CK-MB activity to values that insignificantly differed from the control (39.4±2.8% and 2258.2±179.1 IU/ml, respectively). Simultaneously, 5HD significantly reduced the ATP and ΣAN levels in AAR compared to those in the metilin group and the ATP, ΣAN, and PCr levels compared to the IP group. The results indicate that pharmacological preconditioning by metilin reduced cardiac ischemia/reperfusion injury via the involvement of mitoKATP in the mechanism of metilin action.