Apelin

Cardiometabolic and Antioxidant Properties of Modified C-Terminal Fragments of Apelin in Experimental Cardiac Pathology.

O I Pisarenko, I M Studneva

The development of new drugs for cardiovascular diseases based on endogenous peptide hormones is a field of significant interest, driving intensive experimental research. One promising direction is the synthesis of short bioactive peptides that mimic the effects of larger peptide molecules while offering superior physicochemical properties. Recent studies have shown that C-terminal fragments of the peptide apelin mitigate metabolic and functional impairments following cardiac injury. This review summarizes current literature alongside our own experimental findings regarding the effects of apelin-13, [Pyr1]apelin-13, apelin-12, and its chemically modified analogs on the heart during in vitro and in vivo pathophysiological modeling. The therapeutic spectrum of apelin-12 analogs in the damaged myocardium includes reduced cardiomyocyte death, decreased membrane damage, improved myocardial metabolic status, and the suppression of reactive oxygen species and lipid peroxidation products. These findings highlight the potential of molecular construction of apelin receptor (APJ) agonists with enhanced proteolytic resistance and shelf-life stability as a foundation for a new class of cardiovascular drugs.

International Union of Basic and Clinical Pharmacology. CXXI. Apelin receptor pharmacology in the human cardiovascular system and emerging clinical applications.

Anthony P Davenport, Thomas L Williams, Duuamene Nyimanu +6 more

The apelin receptor binds 2 families of endogenous peptide, apelin and Elabela, but unusually these share little sequence similarity in the N-terminal sequences of the binding domains. Cryo-electron microscopy, X-ray crystallography combined with AlphaFold has yielded a molecular map of the interaction of amino acids with the apelin receptor in complex with endogenous peptides and biased ligands. In the early embryo, the apelin signaling pathway is essential for cardiovascular development, with receptor knockout models displaying severe cardiovascular defects. In adults, the principal short-term effects of [Pyr1]apelin-13, infused into healthy volunteers was increased cardiac output and decreased peripheral resistance without side effects. Importantly, these beneficial effects of systemic apelin were retained in patients with heart failure and pulmonary arterial hypertension. In chronic kidney disease, [Pyr1]apelin-13 showed additional therapeutic potential, increasing glomerular filtration rate while reducing proteinuria. Identification of these favorable actions in disease has sparked the development of more effective agonists with improved pharmacokinetics and pharmacodynamics profiles. Among these are G protein-biased peptide agonists, designed to minimize receptor desensitization by reducing internalization via the β-arrestin pathway. These have shown efficacy in proof-of-concept studies and in animal models of pulmonary arterial hypertension, one of the most promising therapeutic targets. This review focuses on the clinical pharmacology of the apelin receptor, exploring the pathophysiology of diseases where the apelin signaling pathway is dysregulated that have emerged during the last 5 years. SIGNIFICANCE STATEMENT: This review focuses on the pharmacology of the apelin receptor where structural analysis has generated a molecular map of interaction with endogenous ligands, apelin and Elabela, as well as with peptide and small molecule agonists. Novel unbiased and biased apelin agonists are progressing through the clinic targeting pathophysiological conditions where the apelin signaling pathway is dysregulated.

Apelin/APJ Signalling as a Potential Complementary Target for Glucagon-like Peptide-1 Receptor Agonist Therapy in Heart Failure.

Dominic Marcel Alfonso

The Role of the Apelin Receptor in the Pathophysiology of Pulmonary Arterial Hypertension.

Karla M Rada, Alejandra M Zúniga-Muñoz, Yamnia Q Alvarez-Alvarez +8 more

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by endothelial dysfunction, vascular remodeling, and a sustained increase in pulmonary vascular resistance, causing cardiopulmonary damage. The apelin receptor (APJ), a member of the G protein-coupled receptor family, has emerged as an essential modulator of vascular homeostasis. Clinical and preclinical studies have demonstrated that its activation exerts beneficial effects on the progression of PAH. Its main actions include the restoration of endothelial function, reactivation of the BMPR2/SMAD axis, induction of nitric oxide-mediated vasodilation, inhibition of autophagy and the migration of the pulmonary artery smooth muscle cells (PASMCs). Furthermore, its expression and functionality are modulated by epitranscriptomic mechanisms, particularly by microRNAs involved in the post-transcriptional regulation of key genes for vascular homeostasis. These findings position the APJ as a relevant therapeutic target in PAH. However, the clinical application of its agonists still faces pharmacokinetic limitations that restrict their therapeutic use. Therefore, the aim of this review is to gather current information on APJ in the pathophysiology of PAH and focus attention on its potential as a therapeutic target.

SIRT3-dependent enhancement of apelinergic signaling mediates the cardioprotective effects of late-life high-intensity interval training.

Qiaowei Li, Yanmei Song, Qin Liu +4 more

Deficiency in apelinergic signaling (APJ/Apelin) has been shown to accelerate cardiac aging. Given our observation that high-intensity interval training (HIIT) upregulates APJ and Apelin in aged mouse hearts, this study aimed to investigate whether apelinergic signaling mediates the cardioprotective effects of exercise.

Cardioprotective Effects of Apelin in Myocardial Ischemia/Reperfusion Injury: A Systematic Review and Meta-Analysis.

Seyedhesamoddin Khatami, Mohammadsadegh Faghihi, Amirali Zarrin +3 more

Myocardial ischemia/reperfusion (I/R) injury remains a major clinical challenge, because blood flow restoration can exacerbate tissue damage. Apelin, an endogenous peptide acting through the APJ receptor, has demonstrated cardioprotective effects in experimental models. The APJ receptor, a G-protein-coupled receptor widely expressed in cardiovascular tissues, mediates vasodilation, cardiac contractility, and angiogenesis. This systematic review and meta-analysis evaluates its efficacy in myocardial I/R injury. A systematic search in Medline (PubMed), Embase, Scopus, and Web of Science was conducted up to 2024, identifying rodent studies of cardiac I/R injury (Langendorff/in vivo) treated with apelin. Studies on pretreatment or chronic ischemia were excluded. A random-effects meta-analysis reported standardized mean differences with 95% confidence intervals, assessing heterogeneity using the I 2 statistic. From 1765 records, 26 preclinical studies met inclusion criteria. Apelin significantly improved +LVdp/dtmax, -LVdp/dtmax, left ventricular end-diastolic pressure, left ventricular end-systolic pressure, left ventricular ejection fraction, left ventricular developed pressure × heart rate, cardiac output, stroke volume, coronary flow, and left ventricular developed pressure, but did not affect heart rate, mean arterial pressure, left ventricular end-diastolic volume, or left ventricular end-systolic volume. It reduced infarct size, fibrosis, lactate dehydrogenase, malondialdehyde, and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay), while also reducing creatine kinase-MB and improving adenosine triphosphate, energy charge, and phosphocreatine. Meta-regression indicated most outcomes were dose independent, although a few (eg, mean arterial pressure, terminal deoxynucleotidyl transferase dUTP nick end labeling) showed dose-related responses. The risk of bias was high in most studies, and publication bias was observed for some outcomes. Apelin exerts cardioprotective effects in rodent I/R models, enhancing cardiac function and metabolism while reducing infarct size, oxidative stress, and apoptosis. Further standardized preclinical and clinical studies are warranted to optimize dosing protocols and define therapeutic applicability.

Apelin-13 Attenuates Blood-Brain Barrier Dysfunction Following Intracerebral Hemorrhage via Targeting the Keap1/Nrf2 Signaling.

Pingping Guo, Rabeea Siddique, Juanfeng Qian +3 more

Blood-brain barrier (BBB) dysfunction serves as a critical driver of the secondary brain injury following intracerebral hemorrhage (ICH). Previous research has indicated that Apelin-13 demonstrates the potential to alleviate BBB dysfunction in various cerebrovascular disorders. However, the precise mechanisms through which Apelin-13 preserves BBB integrity remain elusive. This study investigated whether Apelin-13 exerted neuroprotective effects by targeting the Keap1/Nrf2 signaling.

Role and therapeutic potential of elabela in renal disease: from molecular mechanisms to clinical applications.

Anni Li, Yuxuan Ye, Huimin Cao +5 more

Elabela (ELA) is a relatively newly identified bioactive micropeptide that functions as the second endogenous ligand for the apelin receptor (APJ). It plays a critical role in diverse physiological processes, including cardiovascular development, blood pressure regulation, and fluid homeostasis. Growing evidence underscores its significance in the pathophysiology of various organ systems, particularly the kidneys. This review aims to comprehensively explore the role of ELA in renal physiology and pathology. We focus on its molecular mechanisms, such as modulating renal hemodynamics, inhibiting fibrosis and inflammation, promoting cellular survival, and its therapeutic potential in acute kidney injury, chronic kidney disease, and hypertensive and diabetic nephropathy. Building upon our research group's previous work, this article places special emphasis on the role of ELA in renal metabolism and its promising application in the treatment of diabetic kidney disease. By synthesizing recent advancements, we seek to elucidate the connection between ELA and kidney health, assessing its potential as a novel therapeutic target for renal diseases.

The Impact of the Apelinergic System on the Cardiovascular System.

Rafał Wyderka, Łukasz Osuch, Bogusława Ołpińska +4 more

The apelin-ELABELA-APJ axis, collectively known as the apelinergic system, has emerged as a key regulator of cardiovascular homeostasis. Acting through G-protein-coupled mechanisms, it modulates vascular tone, cardiac contractility, angiogenesis, fluid balance, and metabolism. Growing evidence indicates that dysregulation of apelinergic signaling contributes to the development and progression of atherosclerosis, hypertension, and heart failure. Experimental studies demonstrate cardioprotective actions of apelin and ELABELA, including anti-fibrotic, anti-inflammatory, vasodilatory, and pro-angiogenic effects, whereas some findings suggest context-dependent pro-atherogenic or vasoconstrictive roles. Clinical data show that circulating apelinergic peptides vary across cardiovascular conditions, being upregulated in acute coronary syndromes and diminished in chronic ischemic or hypertensive disease. In heart failure, early compensatory activation is followed by progressive depletion, and low ELABELA levels correlate with disease severity. Moreover, the apelinergic system may exert anti-arrhythmic effects through modulation of myocardial electrophysiology and structural remodeling. Novel synthetic APJ agonists and stabilized peptide analogs show promising preclinical efficacy in reducing cardiac remodeling, improving contractility, and lowering blood pressure. Altogether, the apelinergic pathway represents a multifaceted modulator and a promising therapeutic target in cardiovascular medicine, warranting further translational studies to elucidate its diagnostic and treatment potential.

ELABELA Ameliorates Atherosclerosis Through Restoring the M1/M2 Macrophage Balance in ApoE-/- Mice.

Le Tang, Xiaoli Yi, Wenting Tan +10 more

Atherosclerosis is a progressive arterial disease characterized by chronic inflammation and plaque formation in blood vessel walls. ELABELA, an endogenous ligand for the G protein-coupled receptor APJ (apelin peptide jejunum, apelin receptor), has multiple pharmacological activities for protecting the cardiovascular system. This study aimed to determine the potential antiatherosclerotic effect of ELABELA and reveal the underlying mechanisms.

Exogenous [Pyr1]apelin-13 prevents bupivacaine-induced cardiotoxicity via the apelin (APJ) receptor.

Chaoxing Chen, Shishi Zhao, Zhengjie Chen +11 more

Abnormal energy metabolism is an important mechanism in the development of bupivacaine-induced cardiotoxicity. Apelin, a peptide derived from adipocytes, plays a pivotal role in both energy metabolism and the regulation of the cardiovascular system, thereby potentially linking it to bupivacaine-induced cardiotoxicity.

ELABELA-32 Alleviates Doxorubicin-Induced Chronic Cardiotoxicity by Inhibiting the TGF-β/Smad Signaling Pathway.

Shuang Zhou, Zhuo Meng, Lin Lu +5 more

Cardiac fibrosis, oxidative stress, and cardiomyocyte apoptosis are key contributors to the progression of doxorubicin (DOX)-induced cardiotoxicity. ELABELA (ELA) is an early endogenous ligand of apelin receptor (APJ/APLNR), which is a G protein-coupled receptor with seven transmembrane domains. Our present study aimed to investigate the protective role and underlying mechanism of ELA-32 in mitigating oxidative stress and fibrosis associated with DOX-induced cardiotoxicity. Using a mouse model of chronic DOX cardiotoxicity (5 mg/kg, i.p, once a week for four times, the total cumulative dose is 20 mg/kg), it was found that exogenous administration of ELA-32 using a microinjection pump significantly improved cardiac function, reduced oxidative stress, and myocardial fibrosis, and enhanced survival. Furthermore, pretreatment with ELA-32 peptide protected rat cardiomyocytes (H9C2 cells) from DOX-induced cytotoxicity in vitro. However, these cardioprotective effects of ELA-32 were no longer observed after activation of the Smad signaling pathway using TGF-β1. In summary, ELA-32 attenuated DOX-induced cardiac fibrosis through by modulating the TGF-β/Smad signaling pathway, thus highlighting its potential as a therapeutic agent for preventing chronic DOX-related cardiotoxicity.

Targeted delivery of apelin using a novel extracellular vesicle platform for pulmonary arterial hypertension treatment.

Jihong Kim, Yong-Soon Choi, Jaehyun Kim +15 more

Pulmonary arterial hypertension (PAH) is a severe disease characterized by endothelial dysfunction, vascular remodeling, and pulmonary artery occlusion, culminating in right ventricular hypertrophy and heart failure. While apelin peptides are promising therapeutic candidates due to their critical role in vascular homeostasis, their efficacy as agonists is limited by insufficient lesion-specific targeting and suboptimal in vivo stability. Here, we developed an engineered extracellular vesicle (EV) platform for precise apelin delivery to PAH lesions, maximizing therapeutic impact. Using interferon-induced transmembrane protein 3 (IFITM3), a type II transmembrane protein, we oriented the apelin peptide on the EV surface with its C-terminus fully exposed, preserving the critical binding interface for functional interaction with the apelin receptor. To further enhance targeting specificity, we integrated the PAH-targeting peptide CARSKNKDC (CAR), which selectively binds to heparan sulfate overexpressed on PAH endothelial cells, into the IFITM3-apelin scaffold, creating CAR-Apelin EVs. This dual-engineered EVs demonstrated exceptional targeting and therapeutic efficacy in PAH models. CAR-Apelin EVs significantly reversed pathological vascular remodeling and improved cardiac function, as evidenced by reduced right ventricular systolic pressure and hypertrophy. Our findings establish CAR-Apelin EVs as a transformative therapeutic strategy, providing a targeted and effective approach to meet critical unmet needs in PAH treatment.

Ero1a, the most strongly hypoxia-induced protein in PASMCs, promotes the development of hypoxia- and monocrotaline-induced pulmonary hypertension in rats.

Xiaojun Hao, Hao Li, Qingli Zeng +2 more

Pulmonary hypertension (PH) is a progressive and life-threatening condition characterized by elevated pressure in the pulmonary circulation, leading to right heart dysfunction and ultimately heart failure. Pulmonary artery smooth muscle cells (PASMCs) are key players in group 3 PH (due to lung diseases and/or hypoxia) progression, where their aberrant proliferation and migration drive vascular remodeling. Dysregulated proteins in PASMCs are critical in PH development. Our research was designed to investigate the most promising potential therapeutic targets for PH.

Insights into the function and research status of membrane protein APJ.

Zhiying Ai, Bo Dong, Jing Chen

APJ, a membrane protein belonging to the G protein-coupled receptor (GPCR) family, was first discovered in 1993. It is activated by endogenous ligands such as Apelin and Elabela, coupling with various G proteins to trigger downstream signaling pathways. APJ is ubiquitously expressed in various organs and tissues, and plays pivotal roles in numerous physiological and pathological processes. This review provides a comprehensive overview of APJ's physiological functions, including its involvement in the cardiovascular system, metabolism, neuroendocrine stress responses, respiratory diseases, and appetite regulation. Furthermore, it discusses the potential of APJ as a biomarker for various tumors and its crucial role in tumor angiogenesis. Additionally, the review covers the development of small molecule antagonists targeting APJ and highlights the major challenges and future prospects in current APJ research. In conclusion, this review offers valuable insights into the multifaceted functions of APJ, its targeting antagonists, existing research challenges, and potential future directions, thereby contributing to further advancements in research and drug development in this field.

Immunohistochemistry and molecular biology studies of apelin and apelin receptor in queen placenta.

Sara Pastore, Cecilia Dall'Aglio, Margherita Maranesi +7 more

Placenta is a tissue where vasculogenesis, blood pressure and blood flow are dramatically important to allow normal embryonic and foetal growth and requires the production of numerous growth factors, hormones and transcription factors. Apelin is a pleiotropic peptide, and its major action relates to energy metabolism, cardiovascular function, body fluid homeostasis via its receptor. The involvement of the apelinergic system during pregnancy in veterinary medicine has been investigated only in bitches. Thereafter, the aim of our study was to investigate, for the first time, presence and distribution of this system in the queen placenta at mid- and end-gestation. Ten pregnant mixed-breed queens were used. The animals were equally divided into two groups based on the stage of pregnancy (mid and end gestation) and, with the written consent of their owners, were subjected to ovariohysterectomy or non-conservative caesarean section. The Real-Time PCR (RT-PCR) analysis showed the presence of transcripts for apelin and its receptor in all the foetal and maternal placenta samples processed. The immunohistochemical (IHC) study evidenced the presence and the distribution of positive immunoreactions for apelin and its receptor in all the samples observed. In particular, in the placental labyrinthic portion, apelin and apelin receptor immunopositivity was evident in the cytoplasm of trophoblasts and endothelial cells. The uterine glands also exhibited a positive immune reaction for apelin and corresponding receptor. Based on our results, apelin and its receptor, also in the queen placenta, could be an important system involved in the physiological development of placenta, embryo and foetal growth.

A Metabolically Stable Apelin-13 Analog Acting as a Potent ITo Potassium Current Blocker with Potential Benefits for Brugada Syndrome.

Juan Antonio Contreras Vite, Alexandria Tiffinger, Léa Théroux +6 more

Apelin serves as the endogenous ligand for the APJ receptor and enhances cardiac contractility without significantly affecting potassium currents. However, its short in vivo half-life limits clinical application, prompting the development of metabolically stable APJ receptor agonists. This study employed the patch-clamp technique to investigate the effects of the C-terminally modified apelin-13-2Nal derivative (2Nal) on action potential dynamics, rapid sodium (INa), and transient potassium (ITO) currents in rat cardiomyocytes. We discovered that 2Nal prolongs ventricular action potential duration by selectively blocking ITo. Dose-response analysis indicated that 2Nal acts as a partial antagonist of ITO, achieving a maximum blockade of 47%, with an apparent EC50 of 0.3 nM, while not affecting INa. Our lab previously found that an imbalance between ITo and INa currents contributes to the development of cardiac arrhythmias in conditions like Brugada syndrome. Currently, few therapeutic options exist to safely address this imbalance, as sodium channel openers cannot restore it, and most ITo blockers are cardiotoxic. The selective blockade of ITo by 2Nal that we describe here helps restore the balance of electrical currents between ITo and INa. Our study presents a novel, safe partial antagonist of ITo that may help prevent arrhythmias associated with Brugada syndrome.

Advances in the therapeutic potentials of ligands of the apelin receptor APJ.

Gerry T M Wagenaar, Gert N Moll

Angiotensin II protein J receptor, APJ, is a type A G protein coupled receptor. Endogenous apelin and elabela peptides stimulate APJ via distinct signalling profiles. A complex signalling map of elabela-stimulated APJ was published in 2022. Dimerization or oligomerization of APJ with itself or other receptor(s) can affect APJ signalling. Apelin has been shown to tolerate mutations and/or modifications at multiple sites without abolishing activity. This offers a great opportunity to design and engineer variants with desired signalling profiles and enhanced resistance to breakdown by peptidases. Several biased agonists with enhanced therapeutic potential have been generated. APJ agonists have therapeutic potential in multiple diseases including cardiovascular, renal, pulmonary and metabolic diseases, and viral infections. APJ antagonists may have therapeutic potential in cancer and retinopathy, and in related diseases in which unwanted angiogenesis is to be halted. A growing understanding of APJ signalling pathways and the robust therapeutic potential of associated ligands for many serious diseases will stimulate the clinical development of APJ ligands.

Activation of APJ Receptors by CMF-019, But Not Apelin, Causes Endothelium-Dependent Relaxation of Spontaneously Hypertensive Rat Coronary Arteries.

Santo Anto, Chengwen Sun, Stephen T O'Rourke

Receptors for the vasoactive adipokine apelin, termed APJ receptors, are G-protein-coupled receptors and are widely expressed throughout the cardiovascular system. APJ receptors can also signal through G-protein-independent pathways, including G-protein-coupled receptor kinase 2 (GRK2), which inhibits endothelial nitric oxide synthase (eNOS) activity and nitric oxide production in endothelial cells. Apelin causes endothelium-dependent, nitric oxide-mediated relaxation of coronary arteries from normotensive animals, but the effects of activating APJ receptor signaling pathways in hypertensive coronary arteries are largely unknown. We hypothesized that apelin-induced relaxation is impaired in coronary arteries from spontaneously hypertensive rats (SHR). Western blot and mRNA analysis revealed increased GRK2 expression in cultured SHR coronary endothelial cells. Apelin failed to cause relaxation in isolated SHR coronary arteries but, in the presence of apelin, relaxations to acetylcholine were impaired. Apelin had no effect on relaxation to diethylamine NONOate. The GRK2 inhibitor, CMPD101, increased apelin-induced phosphorylation of Akt and eNOS in SHR endothelial cells and restored relaxation to apelin in SHR arteries. CMPD101 also blocked the inhibitory effect of apelin on ACh-induced relaxation. Relaxations to the APJ receptor-biased agonist, CMF-019, which preferentially activates the G-protein-dependent pathway with minimal effect on GRK2, were similar in SHR and Wistar Kyoto coronary arteries. Immunoblot analysis in SHR coronary endothelial cells demonstrated that CMF-019 increased Akt and eNOS phosphorylation whereas apelin had no effect. Thus, APJ receptor signaling through GRK2 impairs nitric oxide production or release from SHR endothelial cells. APJ receptor-biased agonists, such as CMF-019, may be more effective than apelin in causing vasodilation of SHR coronary arteries.

Effects and mechanisms of Apelin in treating central nervous system diseases.

Zimeng Huang, Qing Liu, Qixuan Guo +3 more

Apelin, an endogenous ligand of G protein-coupled receptor APJ, is widely distributed in the central nervous system (CNS). It can be divided into such subtypes as Apelin-13, Apelin-17, and Apelin-36 as they have different amino acid structures. All Apelin is widely studied as an adipokine, showing a significant protective effect through regulating apoptosis, autophagy, oxidative stress, angiogenesis, inflammation, and other pathophysiological processes. As an adipokine, Apelin has been found to play a crucial role in cardiovascular disease development. In this paper, we reviewed the effects and mechanisms of Apelin in treating CNS diseases, such as neurotrauma, stroke, spinal cord injury, primary tumors, neurodegenerative diseases, psychiatric diseases, epilepsy, and pain.

Apelinergic System Affects Electrocardiographic Abnormalities Induced by Doxorubicin.

Kasper Buczma, Hubert Borzuta, Katarzyna Kamińska +6 more

Background/Objectives: Anthracyclines remain a pivotal element of numerous tumor management regimens; however, their utilization is associated with a range of adverse effects, the most significant of which is cardiotoxicity. Research is constantly being conducted to identify substances that could be incorporated into ongoing cancer chemotherapy to mitigate anthracycline-induced cardiotoxicity. Recently, the apelinergic system has received a lot of attention in this field due to its involvement in cardiovascular regulation. Therefore, the aim of our study was to investigate the ability of the apelinergic system to inhibit the cardiotoxic effects of anthracycline-doxorubicin (DOX). Methods: In this study, 54 Sprague-Dawley rats were divided into seven groups and received intraperitoneal injections with DOX once a week for 4 consecutive weeks. The osmotic pumps provided a continuous release of NaCl (control groups), apelin-13 and elabela at two different doses, and the apelin receptor (APJ) antagonist ML221. Electrocardiography (ECG) and transthoracic echocardiography (TTE) with assessment of left ventricular (LV) systolic parameters were conducted on the first and last days of the experiment. Results: Lower doses of APJ agonists prevented the prolongation of QT and QTc intervals induced by DOX, while higher doses of these drugs exerted no such effect. The TTE examination confirmed DOX-induced LV systolic dysfunction. Moreover, the TTE examination revealed an improvement in the LV systolic parameters in the DOX-treated groups that were simultaneously administered APJ agonists. Conclusions: Our findings support the use of apelin and elabela as potential cardioprotective agents against anthracycline-induced cardiotoxicity.

Apelin/APJ signaling in IGF-1-induced acute mitochondrial and antioxidant effects in spontaneously hypertensive rat myocardium.

Alejandra M Yeves, Joshua Godoy Coto, Erica V Pereyra +4 more

IGF-1 and apelin are released in response to exercise training with beneficial effects. Previously we demonstrated that a swimming routine is effective to convert pathological into physiological cardiac hypertrophy, and that IGF-1 improves contractility and the redox state, in spontaneously hypertensive rats (SHR). Now, we hypothesize that the apelinergic pathway is involved in the cardioprotective effects of IGF-1 in the SHR. We assessed the redox state and mitochondrial effects of IGF-1 or apelin in the presence/absence of AG1024 or ML221 [pharmacological antagonists of IGF1 (IGF1R) and apelin (APJ) receptors, respectively] in SHR isolated cardiomyocytes or perfused hearts. Acute IGF-1 (10 nmol/L) significantly: -reduced H2O2 production (IGF-1:62 ± 6; control:100 ± 8.1, %), -increased the activity of superoxide dismutase (IGF-1:193 ± 17, control: 100 ± 13,%), -prevented H2O2-induced ΔΨm loss (TMREF10min/F0 min: IGF-1:0.93 ± 0.017, control: 0.72 ± 0.029), -reduced mitochondrial permeability transition pore (mPTP) opening estimated by the calcium retention capacity (nmol/mg protein, IGF-1:251 ± 34, control:112 ± 5), and -increased P-AMPK (IGF-1:129 ± 0.9, control: 100 ± 2%) and P-AKT (IGF-1:143 ± 17 control:100 ± 6, %). These effects were suppressed not only by the antagonism of IGF1R but also of APJ. Moreover, IGF-1 significantly increased APJ (IGF-1:198 ± 29 control:100 ± 15,%) and apelin mRNAs (IGF-1:251 ± 48, control:100 ± 6,%). On the other hand, an equipotent dose of exogenous apelin (50 nmol/L) emulated IGF-1 effects being cancelled by the antagonism of APJ however not by AG1024. IGF-1/IGF1R stimulates the apelinergic pathway, improving the redox balance and mitochondria status in the pathologically hypertrophied myocardium of the SHR.

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan.

Thomas L Williams, Duuamene Nyimanu, Rhoda E Kuc +4 more

Introduction: Pulmonary arterial hypertension (PAH) is characterised by endothelial dysfunction and pathological vascular remodelling, resulting in the occlusion of pulmonary arteries and arterioles, right ventricular hypertrophy, and eventually fatal heart failure. Targeting the apelin receptor with the novel, G protein-biased peptide agonist, MM07, is hypothesised to reverse the developed symptoms of elevated right ventricular systolic pressure and right ventricular hypertrophy. Here, the effects of MM07 were compared with the clinical standard-of-care endothelin receptor antagonist macitentan. Methods: Male Sprague-Dawley rats were randomised and treated with either normoxia/saline, or Sugen/hypoxia (SuHx) to induce an established model of PAH, before subsequent treatment with either saline, macitentan (30 mg/kg), or MM07 (10 mg/kg). Rats were then anaesthetised and catheterised for haemodynamic measurements, and tissues collected for histopathological assessment. Results: The SuHx/saline group presented with significant increases in right ventricular hypertrophy, right ventricular systolic pressure, and muscularization of pulmonary arteries compared to normoxic/saline controls. Critically, MM07 was as at least as effective as macitentan in significantly reversing detrimental structural and haemodynamic changes after 4 weeks of treatment. Discussion: These results support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

Effect of SARS-CoV-2 Infection on Selected Parameters of the Apelinergic System in Repeat Blood Donors.

Marta Stanek, Anna Leśków, Dorota Diakowska

Background: SARS-CoV-2 enters cells primarily by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, thereby blocking its physiological functions, affecting the apelinergic system, and inhibiting the cleavage of its peptides. The appropriate concentration of peptides in the apelinergic system influences the maintenance of homeostasis and protects against cardiovascular diseases. In our research, we determined the level of selected parameters of the apelinergic system-apelin (AP), elabela (ELA), and the apelin receptor (APJ)-in repeat blood donors. Methods: We analyzed 120 serum samples obtained from 30 repeat donors (study group) within four time periods after a SARS-CoV-2 infection: <60 days, 61-90 days, 91-120 days, and >120 days. We compared the results from the study groups with those of the control group, which consisted of 30 serum samples collected from donors donating blood in the years 2018-2019. Results: We observed that the AP, ELA, and APJ concentrations in the control group are higher than in any period in the study group. In the study group, the concentrations of AP and ELA increased in subsequent study periods. AP and ELA concentrations were lower shortly after SARS-CoV-2 transfection and then slowly increased in subsequent periods. APJ concentrations, on the other hand, were lowest at 61-90 days after the infection, but the decrease, relative to their level in healthy subjects, was significant in every period studied. Conclusions: The results suggest that infection with SARS-CoV-2 causes changes in the parameters of the apelinergic system, both after a short period of time has passed since the onset of the SARS-CoV-2 infection, and even up to 4 months after the infection.

Single-cell and spatial transcriptomics reveal apelin/APJ pathway's role in microvessel formation and tumour progression in hepatocellular carcinoma.

Yongfu Zhu, Pengcheng Zhang, Xingxing Huo +4 more

The apelin receptor (APJ) is a key player in tumour angiogenesis, but its role in hepatocellular carcinoma (HCC) remains unclear. This study aims to elucidate the function of the apelin/APJ pathway in HCC using a multi-omics approach and identify potential therapeutic biomarkers. Differentially expressed genes related to the apelin/APJ axis were identified from bulk transcriptomics to reveal HCC-associated disparities. Single-cell and spatial transcriptomics were used to localize and analyse the function of these genes. Machine learning models were constructed to predict outcomes based on apelin/APJ expression, and experimental validation was conducted to explore the pathway's impact on HCC angiogenesis. Single cell analysis revealed an overexpression of APJ/Aplin in the endothelium. The stemness of endothelial cell (EC) with high apelin/APJ was enhanced, as well as the expression of TGFb, oxidative stresses and PI3K/AKT pathway genes. Spatial transcriptomics confirmed that EC populations with high APJ scores were enriched within the tumour. Machine learning models showed high prognostic accuracy. High APJ expression was linked to worse outcomes (p = 0.001), and AUC values were high (1 year, 3 year, 5 year) (0.95, 0.97, 0.98). Immune suppression and non-responsiveness of immune therapy were also seen in high-risk groups. The experimental validation showed that silencing apelin reduced angiogenesis (p  < 0.05), endothelial proliferation, decreased expression of ANG2, KLF2, VEGFA and lower ERK1/2 phosphorylation. Apelin may serve as a potential therapeutic target in HCC, given its role in promoting tumour angiogenesis and poor patient outcomes.

Molecular Changes Implicate Angiogenesis and Arterial Remodeling in Systemic Sclerosis-Associated and Idiopathic Pulmonary Hypertension.

Yuechen Zhou, Tracy Tabib, Mengqi Huang +6 more

Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation of transcriptomic alterations in vascular populations is critical to elucidating cellular mechanisms underlying pathobiology of SSc-associated and idiopathic PH.

Apelin receptor dimer: Classification, future prospects, and pathophysiological perspectives.

Shujuan Hu, Dexiu Wang, Wenkai Liu +3 more

Apelin receptor (APJ), a member of the class A family of G protein-coupled receptor (GPCR), plays a crucial role in regulating cardiovascular and central nervous systems function. APJ influences the onset and progression of various diseases such as hypertension, atherosclerosis, and cerebral stroke, making it an important target for drug development. Our preliminary findings indicate that APJ can form homodimers, heterodimers, or even higher-order oligomers, which participate in different signaling pathways and have distinct functions compared with monomers. APJ homodimers can serve as neuroprotectors against, and provide new pharmaceutical targets for vascular dementia (VD). This review article aims to summarize the structural characteristics of APJ dimers and their roles in physiology and pathology, as well as explore their potential pharmacological applications.

Decreased plasma ELABELA level as a novel screening indicator for heart failure: a cohort and observational study.

Chunju Liu, Jianhua Xiong, Xiaoli Yi +7 more

The predictive power of B-type natriuretic peptide (BNP) and left ventricular ejection fraction (LVEF) is limited by its low specificity in patients with heart failure (HF). Discovery of more novel biomarkers for HF better diagnosis is necessary and urgent. ELABELA, an early endogenous ligand for the G protein-coupled receptor APJ (Apelin peptide jejunum, Apelin receptor), exhibits cardioprotective actions. However, the relationship between plasma ELABELA and cardiac function in HF patients is unclear. To evaluate plasma ELABELA level and its diagnostic value in HF patients, a total of 335 patients with or without HF were recruited for our monocentric observational study. Plasma ELABELA and Apelin levels were detected by immunoassay in all patients. Spearman correlation analysis was used to analyze the correlation between plasma ELABELA or Apelin levels and study variables. The receiver operating characteristic curves were used to access the predictive power of plasma ELABELA or Apelin levels. Plasma ELABELA levels were lower, while plasma Apelin levels were higher in HF patients than in non-HF patients. Plasma ELABELA levels were gradually decreased with increasing New York Heart Association grade or decreasing LVEF. Plasma ELABELA levels were negatively correlated with BNP, left atrial diameter, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and left ventricular posterior wall thickness and positively correlated with LVEF in HF patients. In contrast, the correlation between plasma Apelin levels and these parameters is utterly opposite to ELABELA. The diagnostic value of ELABELA, Apelin, and LVEF for all HF patients was 0.835, 0.673, and 0.612; the sensitivity was 62.52, 66.20, and 32.97%; and the specificity was 95.92, 67.23, and 87.49%, respectively. All these parameters in HF patients with preserved ejection fraction were comparable to those in total HF patients. Overall, plasma ELABELA levels were significantly reduced and negatively correlated with cardiac function in HF patients. Decreased plasma ELABELA levels may function as a novel screening biomarker for HF. A combined assessment of BNP and ELABELA may be a good choice to increase the accuracy of the diagnosis of HF.

Influence of the Apelinergic System on Conduction Disorders in Patients after Myocardial Infarction.

Rafał Wyderka, Dorota Diakowska, Maria Łoboz-Rudnicka +7 more

There is a growing body of evidence for an important role of the apelinergic system in the modulation of cardiovascular homeostasis. The aim of our study was to (1) examine the relationship between apelin serum concentration at index myocardial infarction (MI) and atrioventricular conduction disorders (AVCDs) at 12-month follow-up, and (2) investigate the association between initial apelin concentration and the novel marker of post-MI scar (Q/QRS ratio) at follow-up.

Apelin C-Terminal Fragments: Biological Properties and Therapeutic Potential.

Oleg I Pisarenko, Irina M Studneva

Creation of bioactive molecules for treatment of cardiovascular diseases based on natural peptides is the focus of intensive experimental research. In the recent years, it has been established that C-terminal fragments of apelin, an endogenous ligand of the APJ receptor, reduce metabolic and functional disorders in experimental heart damage. The review presents literature data and generalized results of our own experiments on the effect of apelin-13, [Pyr]apelin-13, apelin-12, and their chemically modified analogues on the heart under normal and pathophysiological conditions in vitro and in vivo. It has been shown that the spectrum of action of apelin peptides on the damaged myocardium includes decrease in the death of cardiomyocytes from necrosis, reduction of damage to cardiomyocyte membranes, improvement in myocardial metabolic state, and decrease in formation of reactive oxygen species and lipid peroxidation products. The mechanisms of protective action of these peptides associated with activation of the APJ receptor and manifestation of antioxidant properties are discussed. The data presented in the review show promise of the molecular design of APJ receptor peptide agonists, which can serve as the basis for the development of cardioprotectors that affect the processes of free radical oxidation and metabolic adaptation.