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Apelin/APJ relieve diabetic cardiomyopathy by reducing microvascular dysfunction.

ABSTRACT: Microcirculatory injuries had been reported to be involved in diabetic cardiomyopathy, which was mainly related to endothelial cell dysfunction. Apelin, an adipokine that is upregulated in diabetes mellitus, was reported to improve endothelial cell dysfunction and attenuate cardiac insufficiency induced by ischemia and reperfusion. Therefore, it is hypothesized that apelin might be involved in alleviating endothelial cell dysfunction and followed cardiomyopathy in diabetes mellitus. The results showed that apelin improved endothelial cell dysfunction via decreasing apoptosis and expression of adhesion molecules and increasing proliferation, angiogenesis, and expression of E-cadherin, VEGFR 2 and Tie-2 in endothelial cells, which resulted in the attenuation of the capillary permeability in cardiac tissues and following diabetic cardiomyopathy. Meanwhile, the results from endothelial cell-specific APJ knockout mice and cultured endothelial cells confirmed that the effects of apelin on endothelial cells were dependent on APJ and the downstream NFκB pathways. In conclusion, apelin might reduce microvascular dysfunction induced by diabetes mellitus via improving endothelial dysfunction dependent on APJ activated NFκB pathways.

SUBMITTER: Li B

PROVIDER: S-EPMC8052525 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Icariin Ameliorates Diabetic Cardiomyopathy Through Apelin/Sirt3 Signalling to Improve Mitochondrial Dysfunction.

Project description:Myocardial contractile dysfunction in diabetic cardiomyocytes is a significant promoter of heart failure. Herein, we investigated the effect of icariin, a flavonoid monomer isolated from Epimedium, on diabetic cardiomyopathy (DCM) and explored the mechanisms underlying its unique pharmacological cardioprotective functions. High glucose (HG) conditions were simulated in vitro using cardiomyocytes isolated from neonatal C57 mice, while DCM was stimulated in vivo in db/db mice. Mice and cardiomyocytes were treated with icariin, with or without overexpression or silencing of Apelin and Sirt3 via transfection with adenoviral vectors (Ad-RNA) and specific small hairpin RNAs (Ad-sh-RNA), respectively. Icariin markedly improved mitochondrial function both in vivo and in vitro, as evidenced by an increased level of mitochondrial-related proteins via western blot analysis (PGC-1?, Mfn2, and Cyt-b) and an increased mitochondrial membrane potential, as observed via JC-1 staining. Further, icariin treatment decreased cardiac fibrogenesis (Masson staining), and inhibited apoptosis (TUNEL staining). Together, these changes improved cardiac function, according to multiple transthoracic echocardiography parameters, including LVEF, LVSF, LVESD, and LVEDD. Moreover, icariin significantly activated Apelin and Sirt3, which were inhibited by HG and DCM. Importantly, when Ad-sh-Apelin and Ad-sh-Sirt3 were transfected in cardiomyocytes or injected into the heart of db/db mice, the cardioprotective effects of icariin were abolished and mitochondrial homeostasis was disrupted. Further, it was postulated that since Ad-Apelin induced different results following increased Sirt3 expression, icariin may have attenuated DCM development by preventing mitochondrial dysfunction through the Apelin/Sirt3 pathway. Hence, protection against mitochondrial dysfunction using icariin may prove to be a promising therapeutic strategy against DCM in diabetes.

| S-EPMC7106769 | biostudies-literature

Effect of L-Carnitine Supplementation on Apelin and Apelin Receptor (Apj) Expression in Cardiac Muscle of Obese Diabetic Rats.

Project description:Objective:L-carnitine (LC) has been shown to protect cardiac metabolism in diabetes patients with cardiovascular diseases (CVDs). Apelin, a newly discovered adipocytokines, is an important regulator of cardiac muscle function; however, the role of the level of expression of Apelin axis in improvement of cardiac function by LC in diabetic patients, is not clear. In the present study, obese insulin-resistant rats were used to determine the effect of LC, when given orally with a high-calorie diet, on Apelin and Apelin receptor (Apj) expression in cardiac muscle. Materials and Methods:In this experimental study, rats were fed with high-fat/high-carbohydrate diet for five weeks and subsequently were injected with streptozotocin 30 mg/kg for induction of obesity and insulin resistance. After confirming the induction of diabetes (serum glucose above 7.5 mmol/L), the animals received LC 300 mg/kg in drinking water for 28 days. On days 0, 14 and 28 after treatment, cardiac Apelin and Apj gene expression was evaluated by real time polymerase chain reaction (PCR) analysis. Serum levels of insulin, Apelin, glucose, tumor necrosis factor-? (TNF-?), interleukin-1? (IL-1?) and the homeostasis model assessment of insulin resistance (HOMA-IR) were also measured using commercial kits. Results:Cardiac Apelin and Apj expression and serum Apelin were increased in obese rats, while LC supplementation decreased the serum levels of Apelin and down-regulated Apelin and Apj expression in cardiac muscle. These changes were associated with reduced insulin resistance markers and serum inflammatory factors and improved lipid profile. Conclusion:We concluded that LC supplementation could attenuate the over-expression of Apelin axis in heart of diabetic rats, a novel mechanism by which LC improves cardiovascular complications in diabetic patients.

| S-EPMC6005003 | biostudies-literature

The Apelin/APJ System in Psychosis and Neuropathy.

Project description:Apelin, an endogenous neuropeptide, has been identified as the cognate ligand for the G-protein-coupled receptor APJ. Apelin, APJ messenger RNA, and protein are widely expressed in the central nervous system and peripheral tissues of humans and animals. The apelin/APJ system has been implicated in diverse physiological and pathological processes. The present article reviews the progress of the latest research investigating the apelin/APJ system in pain, depression, anxiety, memory, epilepsy, neuroprotection, stroke, and brain injury and protection, and highlights its promising potential as a therapeutic target for treatment of psychosis and neuropathy.

| S-EPMC7082832 | biostudies-literature

Identification of potent pyrazole based APELIN receptor (APJ) agonists.

Project description:The apelinergic system comprises the apelin receptor and its cognate apelin and elabela peptide ligands of various lengths. This system has become an increasingly attractive target for pulmonary and cardiometabolic diseases. Small molecule regulators of this receptor with good drug-like properties are needed. Recently, we discovered a novel pyrazole based small molecule agonist 8 of the apelin receptor (EC50 = 21.5 µM, Ki = 5.2 µM) through focused screening which was further optimized to initial lead 9 (EC50 = 0.800 µM, Ki = 1.3 µM). In our efforts to synthesize more potent agonists and to explore the structural features important for apelin receptor agonism, we carried out structural modifications at N1 of the pyrazole core as well as the amino acid side-chain of 9. Systematic modifications at these two positions provided potent small molecule agonists exhibiting EC50 values of <100 nM. Recruitment of β-arrestin as a measure of desensitization potential of select compounds was also investigated. Functional selectivity was a feature of several compounds with a bias towards calcium mobilization over β-arrestin recruitment. These compounds may be suitable as tools for in vivo studies of apelin receptor function.

| S-EPMC7055011 | biostudies-literature

Apelin/Elabela-APJ: a novel therapeutic target in the cardiovascular system.

Project description:Apelin and Elabela (ELA) are endogenous ligands of angiotensin domain type 1 receptor-associated proteins (APJ). Apelin/ELA-APJ signal is widely distributed in the cardiovascular system of fetuse and adult. The signal is involved in the development of the fetal heart and blood vessels and regulating vascular tension in adults. This review described the effects of apelin/ELA-APJ on fetal (vasculogenesis and angiogenesis) and adult cardiovascular function [vascular smooth muscle cell (VSMC) proliferation, vasodilation, positive myodynamia], and relative diseases [eclampsia, hypertension, pulmonary hypertension, heart failure (HF), myocardial infarction (MI), atherosclerosis, etc.] in detail. The pathways of apelin/ELA-APJ regulating cardiovascular function and cardiovascular-related diseases are summarized. The drugs developed based on apelin and ELA suggests APJ is a prospective strategy for cardiovascular disease therapy.

| S-EPMC7154429 | biostudies-literature

Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension.

Project description:The G-protein-coupled receptor APJ and its ligand apelin are highly expressed in the pulmonary vasculature, but their function in this vascular bed is unclear. We hypothesized that disruption of apelin signaling would lead to worsening of the vascular remodeling associated with pulmonary hypertension (PH).We found that apelin-null mice developed more severe PH compared with wild-type mice when exposed to chronic hypoxia. Micro-computed tomography of the pulmonary arteries demonstrated significant pruning of the microvasculature in the apelin-null mice. Apelin-null mice had a significant reduction of serum nitrate levels. This was secondary to downregulation of endothelial nitric oxide synthase (eNOS), which was associated with reduced expression of Kruppel-like factor 2 (KLF2), a known regulator of eNOS expression. In vitro knockdown studies targeting apelin in human pulmonary artery endothelial cells demonstrated decreased eNOS and KLF2 expression, as well as impaired phosphorylation of AMP-activated kinase and eNOS. Moreover, serum apelin levels of patients with PH were significantly lower than those of controls.These data demonstrate that disruption of apelin signaling can exacerbate PH mediated by decreased activation of AMP-activated kinase and eNOS, and they identify this pathway as a potentially important therapeutic target for treatment of this refractory human disease.

| S-EPMC3113525 | biostudies-literature

Apelin/APJ targeted microRNAs in pulmonary artery endothelial cells

Project description:Evaluation of microRNAs that are downstream of apelin/APJ signaling in the pulmonary artery endothelial cells.

2012-12-04 | GSE42343 | GEO

FoxO1 inhibition by apelin/APJ signaling in endothelial cells

Project description:Evaluation of gene transcripts that are downstream of apelin/APJ and FoxO1 signaling in HUVECs

2017-10-02 | GSE67390 | GEO

Apelin promotes diabetic nephropathy by inducing podocyte dysfunction via inhibiting proteasome activities.

Project description:Podocyte injuries are associated with progression of diabetic nephropathy (DN). Apelin, an adipocyte-derived peptide, has been reported to be a promoting factor for DN. In this study, we aim to determine whether apelin promotes progression of DN by inducing podocyte dysfunction. kk-Ay mice were used as models for DN. Apelin and its antagonist, F13A were intraperitoneally administered for 4 weeks, respectively. Renal function and foot process proteins were analysed to evaluate the effects of apelin on kk-Ay mice and podocytes. Apelin increased albuminuria and decreased podocyte foot process proteins expression in kk-Ay mice, which is consistent with the results that apelin receptor (APLNR) levels increased in glomeruli of patients or mice with DN. In cultured podocytes, high glucose increased APLNR expression and apelin administration was associated with increased permeability and decreased foot process proteins levels. All these dysfunctions were associated with decreased 26S proteasome activities and increased polyubiquitinated proteins in both kk-Ay mice and cultured podocytes, as demonstrated by 26S proteasome activation with cyclic adenosine monophosphate (cAMP) or oleuropein. These effects seemed to be related to endoplasmic reticulum (ER) stress, as apelin increased C/EBP homologous protein (CHOP) and peiFα levels while cAMP or oleuropein reduced it in high glucose and apelin treated podocytes. These results suggest that apelin induces podocyte dysfunction in DN through ER stress which was induced by decreased proteasome activities in podocytes.

| S-EPMC4568931 | biostudies-literature

Comparing High-Intensity Interval Training (HIIT) and Continuous Training on Apelin, APJ, NO, and Cardiotrophin-1 in Cardiac Tissue of Diabetic Rats.

Project description:Background and Aims:Exercise activity is an important method for managing type 2 diabetes. This investigation examined the HIIT and continuous training on apelin, APJ receptor, NO, and cardiotrophin-1 in the cardiac tissue of diabetic rats. Methods:The animals were categorized into 3 groups of HIIT, continuous (CO), and control (C) (all animals were sacrificed immediately and 2 days after exercise training period). Rats underwent the treadmill exercise program either HIIT (12 bouts at 90-95% of VO2 max with 60?s rest at 50% of VO2 max) or CO (60-65% VO2 max for 40?min). Protocols performed 5 days per week for 8 weeks. Apelin, APJ receptor, NO, and cardiotrophin-1 protein expressions were measured using the Western blotting method in the left ventricle. Results:Immediately after HIIT and CO exercise protocols, apelin and CT-1 protein showed a significant difference in contrast by the C-0 group (p < 0.01). However, NO values were substantially higher in HIIT-0 compared to C-0 and CO-0 groups rats (p < 0.01). After two days of exercise protocols, apelin and NO protein showed a significant increase in HIIT and CO groups in contrast to the C animals (p < 0.01). Moreover, APJ and CT-1 protein significantly upregulated in CO-2 and HIIT-2 compared to the other groups (p < 0.01). Conclusions:This study indicates that exercise training, despite the type, is an efficient method to modify apelin, APJ receptor, NO, and cardiotrophin-1 values in animals with type 2 diabetes.

| S-EPMC7474749 | biostudies-literature

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