The Protective Effects and Mechanisms of Apelin/APJ System on Ischemic Stroke: A Promising Therapeutic Target

Tian, Yuan; Chen, Ruijiao; Jiang, Yunlu; Bai, Bo; Yang, Tongju; Liu, Haiqing

doi:10.3389/fneur.2020.00075

Cited by 22 publications

(11 citation statements)

References 100 publications

(127 reference statements)

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“…Він був відкритий у 1992 році і вважається адипокіном, так як секретується адипоцитами людини. Апелін та його рецептори (зокрема G-білковий рецептор апеліну, стара назва -APG-рецептор) в високих концентраціях були виявленні в кардіоміоцитах, ендотелії судин, клітинах гладенької мускулатури, головному мозку, нирках та наднирниках [1,8,17]. Рецептори апеліну регулюють багаточисельні біологічні функції і приймають участь в підтриманні серцево-судинного і метабол-ічного гомеостазу [4,11].…”

Section: вступunclassified

“…Встановлено, що рівень апеліну суттєво знижується вже на другу добу у пацієнтів з гострим інфарктом міокарда та у хворих на ішемічний інсульт. Слід зазначити, що рівень апеліну значно нижчий у курців в порівнянні з тими, хто немає цієї шкідливої звички [8,17,21] [3,14,20].…”

Section: вступunclassified

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Clinical and instrumental profile of patients with stage II essential hypertension with different forms of extrasystoles according to the level of apelin-13

Іvankova¹,

Kuzmіnova²,

Іванов³

2021

Rep. of Vinnytsia Nation. Med. Univ.

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Annotation. Essential hypertension (EH) is one of the leading causes of disability and mortality among cardiovascular diseases, so today new metabolic markers of cardiovascular risk are being actively studied. One of them is apelin-13. Objective – to evaluate the clinical and instrumental profile of patients with stage II hypertension with different forms of extrasystoles and different neurohumoral background – conditionally high/low serum apelin-13 levels. 156 patients with stage II essential hypertension were examined. 124 of them had frequent symptomatic extrasystoles, 32 patients had no arrhythmias and were considered to the comparison group. 30 practically healthy normotensive persons were considered to the control group. All patients underwent a complete clinical and anthropometric examination, blood pressure measurement, automatic daily blood pressure monitoring, daily electrocardiogram monitoring, echocardiography and the assessment of serum apelin-13 level. For statistical analysis, the procedure of non-linear data estimation was chosen, namely logistic regression or logit model. To form the basic statistical matrix of the analysis, we used clinical-instrumental and laboratory indicators, which passed a preliminary correlation analysis of Spearman with the level of apelin-13 serum and found a significant correlation (p<0.05). In the course of the logistic analysis at the final model, which allowed to predict “background of apelin” in patients with stage II EH entered 4 independent factors that revealed statistically significant (p<0.05) correlations with the initial parameter: the value of the systolic arterial pressure time index in%, the index of the left atrium in mm/m2, the average number of ventricular extrasystoles for 1 hour and the level of total cholesterol in plasma in mmol/l. The last indicator showed the least informativeness in predicting of the apelin-13 serum level. Interpreting the data of the obtained logit regression model, it should be said that in patients with EH of increasing the value of the systolic arterial pressure time index, the index of the left atrium and the average value of ventricular extrasystoles during 1 hour and decrease total cholesterol level in plasma increase the probability of determining relatively low (<920 pg/ml) and at the same time reduce the probability of determining a relatively high (≥920 pg/ml) level of apelin serum. These data also show that the highest informativeness in predicting the level of apelin-13 in patients with EH was the total number of ventricular extrasystole per hour. So, a high “apelin background” (≥920 pg/ml) in patients with EH will be accompanied by a benign course of the disease, so an increase serum apelin-13 in patients with EH should be considered as positive neurohumoral changes that promote cardioprotection, improve prognosis course of the disease and reduce cardiovascular risk.

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Section: вступunclassified

Clinical and instrumental profile of patients with stage II essential hypertension with different forms of extrasystoles according to the level of apelin-13

Іvankova¹,

Kuzmіnova²,

Іванов³

2021

Rep. of Vinnytsia Nation. Med. Univ.

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“…APELA is a novel endogenous peptide ligand that activates the APJ receptor axis and is cardioprotective against HTN, MI, pulmonary arterial hypertension, and heart failure [37,38]. Recently, studies have shown that the apelin/APJ axis possess neuroprotective effects by inhibiting neuronal apoptosis and improving functional recovery in IS through diverse mechanisms, including suppressing inflammatory responses, modulating autophagy, and promoting angiogenesis [39]. MARCH1 has been identified as a susceptibility locus for MI and HTN in Japanese [40], and regarding IS, was included as 1 of the 31 SNPs significantly associated with IS in an initial EWAS [41].…”

Section: Discussionmentioning

confidence: 99%

Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia

et al. 2021

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Background Hypertension (HTN), diabetes mellitus (DM), and dyslipidemia (DL) are well-known risk factors of cardiovascular disease (CVD), but not all patients develop CVDs. Studies have been limited investigating genetic risk of CVDs specific to individuals with metabolic diseases. This study aimed to identify disease-specific and/or common genetic loci associated with CVD susceptibility in chronic metabolic disease patients. Methods We conducted a genome-wide association study (GWAS) of a multiple case–control design with data from the City Cohort within Health EXAminees subcohort of the Korean Genome and Epidemiology Study (KoGES_HEXA). KoGES_HEXA is a population-based prospective cohort of 173,357 urban Korean adults that had health examinations at medical centers. 42,393 participants (16,309 HTN; 5,314 DM; 20,770 DL) were analyzed, and each metabolic disease group was divided into three CVD case-controls: coronary artery disease (CAD), ischemic stroke (IS), and cardio-cerebrovascular disease (CCD). GWASs were conducted for each case–control group with 7,975,321 imputed single nucleotide polymorphisms using the Phase 3 Asian panel from 1000 Genomes Project, by logistic regression and controlled for confounding variables. Genome-wide significant levels were implemented to identify important susceptibility loci. Results Totaling 42,393 individuals, this study included 16,309 HTN (mean age [SD], 57.28 [7.45]; 816 CAD, 398 IS, and 1,185 CCD cases), 5,314 DM (57.79 [7.39]; 361 CAD, 153 IS, and 497 CCD cases), and 20,770 DL patients (55.34 [7.63]; 768 CAD, 295 IS, and 1,039 CCD cases). Six genome-wide significant CVD risk loci were identified, with relatively large effect sizes: 1 locus in HTN (HTN-CAD: 17q25.3/CBX8-CBX4 [OR, 2.607; P = 6.37 × 10−9]), 2 in DM (DM-IS: 4q32.3/MARCH1-LINC01207 [OR, 5.587; P = 1.34 × 10−8], and DM-CCD: 17q25.3/RPTOR [OR, 3.511; P = 1.99 × 10−8]), and 3 in DL (DL-CAD: 9q22.2/UNQ6494-LOC101927847 [OR, 2.282; P = 7.78 × 10−9], DL-IS: 3p22.1/ULK4 [OR, 2.162; P = 2.97 × 10−8], and DL-CCD: 2p22.2/CYP1B1-CYP1B1-AS1 [OR, 2.027; P = 4.24 × 10−8]). Conclusions This study identified 6 susceptibility loci and positional candidate genes for CVDs in HTN, DM, and DL patients using an unprecedented study design. 1 locus (17q25.3) was commonly associated with CAD. These associations warrant validation in additional studies for potential therapeutic applications.

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“…Since its discovery as the second endogenous ligand of the APJ receptor (Szokodi et al, 2002), Elabela has received growing interest given the pharmacological role of the Apelin-APJ system in a variety of physiological and pathological processes, which include cardiovascular and kidney diseases, but also metabolic disorders, such as insulin resistance/type 2 diabetes and obesity, cancer development and progression, ischemic stroke as well as neurodegenerative diseases (Scimia et al, 2012;Chen et al, 2018;Coquerel et al, 2018;Wysocka et al, 2018;Castan-Laurell et al, 2019;Huang et al, 2019;Kinjo et al, 2020;Luo et al, 2020;Masoumi et al, 2020;Tian et al, 2020). In particular, similar to Ape13, Elabela which binds to APJ and activates the β-arrestin-2 and G αi signaling pathways exerts protective effects against various cardiovascular diseases and related complications (Coquerel et al, 2018;Kuba et al, 2019;Liu et al, 2019;Chen et al, 2020a;Liu et al, 2020;Ma et al, 2020;Xu, 2020).…”

Section: Discussionmentioning

confidence: 99%

Elabela Protects Spontaneously Hypertensive Rats From Hypertension and Cardiorenal Dysfunctions Exacerbated by Dietary High-Salt Intake

et al. 2021

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Objectives: Arterial hypertension, when exacerbated by excessive dietary salt intake, worsens the morbidity and mortality rates associated with cardiovascular and renal diseases. Stimulation of the apelinergic system appears to protect against several circulatory system diseases, but it remains unknown if such beneficial effects are conserved in severe hypertension. Therefore, we aimed at determining whether continuous infusion of apelinergic ligands (i.e., Apelin-13 and Elabela) exerted cardiorenal protective effects in spontaneously hypertensive (SHR) rats receiving high-salt diet.Methods: A combination of echocardiography, binding assay, histology, and biochemical approaches were used to investigate the cardiovascular and renal effects of Apelin-13 or Elabela infusion over 6 weeks in SHR fed with normal-salt or high-salt chow.Results: High-salt intake upregulated the cardiac and renal expression of APJ receptor in SHR. Importantly, Elabela was more effective than Apelin-13 in reducing high blood pressure, cardiovascular and renal dysfunctions, fibrosis and hypertrophy in high-salt fed SHR. Unlike Apelin-13, the beneficial effects of Elabela were associated with a counter-regulatory role of the ACE/ACE2/neprilysin axis of the renin-angiotensin-aldosterone system (RAAS) in heart and kidneys of salt-loaded SHR. Interestingly, Elabela also displayed higher affinity for APJ in the presence of high salt concentration and better resistance to RAAS enzymes known to cleave Apelin-13.Conclusion: These findings highlight the protective action of the apelinergic system against salt-induced severe hypertension and cardiorenal failure. As compared with Apelin-13, Elabela displays superior pharmacodynamic and pharmacokinetic properties that warrant further investigation of its therapeutic use in cardiovascular and kidney diseases.

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The Protective Effects and Mechanisms of Apelin/APJ System on Ischemic Stroke: A Promising Therapeutic Target

Cited by 22 publications

References 100 publications

Clinical and instrumental profile of patients with stage II essential hypertension with different forms of extrasystoles according to the level of apelin-13

Clinical and instrumental profile of patients with stage II essential hypertension with different forms of extrasystoles according to the level of apelin-13

Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia

Elabela Protects Spontaneously Hypertensive Rats From Hypertension and Cardiorenal Dysfunctions Exacerbated by Dietary High-Salt Intake

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