Apelin-13: a novel approach to suppressing renin production in RVHT.

Renovascular hypertension (RVHT) is characterized by renal artery stenosis and overactivated renin-angiotensin system (RAS). Apelin, known for its negative modulation of RAS, has protective effects against cardiovascular diseases. The role and mechanisms of the primary active form of apelin, apelin-13, in RVHT are unclear. In this study, male Sprague-Dawley rats were divided into control, two-kidney one-clip (2K1C) model, and 2K1C with apelin-13 treatment groups. Renin expression was analyzed using immunohistochemistry and molecular techniques. Full-length (pro)renin receptor (fPRR) and soluble PRR (sPRR) levels were assessed via Western blotting, and cAMP levels were measured using ELISA. Plasma renin content, plasma renin activity (PRA), angiotensin II (ANG II), and sPRR levels were determined by ELISA. Human Calu-6 and mouse As4.1 cells were used to investigate renin production mechanisms. The 2K1C model exhibited increased systolic blood pressure, plasma renin content, PRA, sPRR, and ANG II levels, while apelin-13 treatment reduced these elevations. Apelin-13 inhibited cAMP production, renin mRNA expression, protein synthesis, and PRR/sPRR protein expression in renal tissue. In Calu-6 cells, cAMP-induced fPRR and site-1 protease (S1P)-derived sPRR expression, which was blocked by cAMP-responsive element-binding protein (CREB) inhibition. Apelin-13 suppressed cAMP elevation, CREB phosphorylation, fPRR/sPRR protein expression, and renin production. Recombinant sPRR (sPRR-His) stimulated renin production, which was inhibited by the PRR decoy peptide PRO20 and S1P inhibitor PF429242. These findings suggest that apelin-13 inhibits plasma renin expression through the cAMP/PKA/sPRR pathway, providing a potential therapeutic approach for RVHT. Understanding the regulation of renin production is crucial for developing effective treatments.NEW & NOTEWORTHY Our research elucidated that apelin-13 inhibits renin production through the cAMP/PKA/soluble (pro)renin receptor pathway, presenting a promising therapeutic approach for renovascular hypertension (RVHT) by targeting renin expression mechanisms. These findings underscore the potential of apelin-13 as a novel strategy to address RVHT.

Fluorinated apelin-13 mediates neuroprotective effects in multiple sclerosis models.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or immunosuppressive drugs acting on the inflammatory component. However, these treatments do not adequately address the crucial aspect of neuroprotection. Recently, an association between an altered balance of adipokines and MS has been proposed as both a risk factor for developing MS and a chronic disease aggravating factor. Specifically, a decrease of apelin plasma levels in MS patients compared to controls correlates with the number of relapses and disease severity. Here we report a dramatic downregulation of apelin levels in the CNS of EAE mice which is also detected in MS patients brain samples compared to controls. Exploiting innovative design and synthesis techniques, we engineered a novel fluorinated apelin-13 peptide characterized by enhanced plasmatic stability compared to its native counterpart. With this peptide, we assessed the potential therapeutic benefits of apelin preventive supplementation in the EAE mouse model. We show that the fluorinated Apelin-13 peptide ameliorates EAE clinical score and preserves myelin content in the EAE MOG model recapitulating the progressive form of disease. These results combined with ex-vivo experiments in brain organotypic slices and in vitro studies in neurons and primary microglia and macrophages suggest that apelin has neuroprotective effects and influences the microglia/macrophages function.

The impact of apelin-13 on cisplatin-induced endocrine pancreas damage in rats: an in vivo study.

Apelin-13 is a peptide hormone that regulates pancreatic endocrine functions, and its benefits on the endocrine pancreas are of interest. This study aims to investigate the potential protective effects of apelin-13 in cisplatin-induced endocrine pancreatic damage. Twenty-four rats were divided into four groups: control, apelin-13, cisplatin, and cisplatin + apelin-13. Caspase-3, TUNEL, and Ki-67 immunohistochemical staining were used as markers of apoptosis and mitosis. NF-κB/p65 and TNFα were used to show inflammation. ß-cells and α-cells were also evaluated with insulin and glucagon staining in the microscopic examination. Pancreatic tissue was subjected to biochemical analyses of glutathione (GSH) and malondialdehyde (MDA). Apelin-13 ameliorated cisplatin-induced damage in the islets of Langerhans. The immunopositivity of apelin-13 on ß-cells and α-cells was found to be increased compared to the cisplatin group (p = 0.001, p = 0.001). Mitosis and apoptosis were significantly higher in the cisplatin group (p = 0.001). Apelin-13 reduced TNFα, NF-κB/p65 positivity, and apoptosis caused by cisplatin (p = 0.001, p = 0.001, p = 0.001). While cisplatin caused a significant increase in MDA levels (p = 0.001), apelin caused a significant decrease in MDA levels (p = 0.001). The results demonstrated a significant decrease in pancreatic tissue GSH levels following cisplatin treatment (p = 0.001). Nevertheless, apelin-13 significantly enhanced cisplatin-induced GSH reduction (p = 0.001). On the other hand, the serum glucose level, which was measured as 18.7 ± 2.5 mmol/L in the cisplatin group, decreased to 13.8 ± 0.7 mmol/L in the cisplatin + apelin-13 group (p = 0.001). The study shows that apelin-13 ameliorated cisplatin-induced endocrine pancreas damage by reducing oxidative stress and preventing apoptosis.

Protective effect of apelin-13 on ventilator-induced acute lung injury.

BACKGROUND: Mechanical Ventilation (MV) is an essential mechanism of life support in the clinic. It may also lead to ventilator-induced acute lung injury (VILI) due to local alveolar overstretching and/or repeated alveolar collapse. However, the pathogenesis of VILI is not completely understood, and its occurrence and development may be related to physiological processes such as the inflammatory response, oxidative stress, and apoptosis. Some studies have found that the the apelin/APJ axis is an endogenous antagonistic mechanism activated during acute respiratory distress syndrome(ARDS), that can counteract the injury response and prevent uncontrolled lung injury. To indicate that apelin-13 plays a protective role in VILI, an animal model of VILI was established in this study to explore whether apelin-13 can alleviate VILI in rats by inhibiting inflammation, apoptosis and oxidative stress. METHODS: SD rats were divided into four groups: control, high tidal volume, high tidal volume + normal saline and high tidal volume + apelin-13. After tracheotomy, the rats in control maintained spontaneous breathing, and the other rats were connected to the small animal ventilator for 4 h to establish the rat VILI model. The mRNA expression of apelin was measured by real-time quantitative polymerase chain reaction(qRT-PCR), immunofluorescence and Western blotting(WB) were used to detect the expression level of APJ, and WB was used to detect the expression of the apoptotic proteins Bax and bcl-2. The degree of lung injury was evaluated by pathological staining of lung tissue,W/D ratio, and BALF total protein concentration. The expression of inflammatory factors(IL-1ß, IL-6, TNF-α) in alveolar lavage fluid was measured using ELISA. The activities of MPO and cat and the content of MDA, an oxidative product, in lung tissue were measured to evaluate the degree of oxidative stress in the lung. RESULTS: After treatment with apelin-13, the apelin/APJ axis in the lung tissue of VILI model rats was activated, and the effect was further enhanced. The pathological damage of lung tissue was alleviated, the expression of the antiapoptotic protein Bcl-2 and the proapoptotic protein Bax was reversed, and the levels of the inflammatory cytokines IL-1ß, IL-6, TNF-α levels were all decreased. MPO activity and MDA content decreased, while CAT activity increased. CONCLUSION: The apelin/apj axis is activated in VILI. Overexpression of apelin-13 further plays a protective role in VILI, mainly by including reducing pathological damage, the inflammatory response, apoptosis and antioxidant stress in lung tissue, thus delaying the occurrence and development of VILI.

Circ_0043314 Modulates Proliferation and Apoptosis of Ovarian Granulosa Cells in Polycystic Ovarian Syndrome via the MicroRNA-146b-3p/Apelin 13 Axis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. At present, the pathogenesis has not been clarified, and the clinical application of drugs and lifestyle intervention may not prevent disease progression. This study aimed to investigate how circ_0043314 regulates ovarian granulosa cell biological functions to provide a theoretical basis for the treatment of patients with PCOS. MicroRNA (miR)-146b-3p/Apelin 13 axis was used to investigate the mechanism by which circ_0043314 regulated ovarian granulosa cell proliferation and apoptosis in PCOS via miR-146b-3p/Apelin 13 axis. Participants/Materials, Methods: Ovarian tissues (cortical tissues) from 35 PCOS patients and 35 normal controls, as well as HEK293T and human ovarian granulosa cell line (KGN, COV434), were included in this study. We examined the expression levels of circ_0043314, miR-146b-3p, and Apelin 13 in PCOS tissues. Ovarian granulosa cells were transfected with corresponding plasmids to clarify the influence of circ_0043314, miR-146b-3p, or Apelin 13 on proliferation and apoptosis of ovarian granulosa cells through MTT and flow cytometry assays. Moreover, the relationships among circ_0043314, miR-146b-3p, and Apelin 13 were analyzed through dual-luciferase and RNA immunoprecipitation assays. RESULTS: Circ_0043314 and Apelin 13 were highly expressed and miR-146b-3p was lowly expressed in ovarian tissues of PCOS compared with non-PCOS controls. Downregulation of circ_0043314 or upregulation of miR-146b-3p hindered ovarian granulosa cell proliferation and advanced its apoptosis. Downregulation of miR-146b-3p reversed the impacts of downregulation of circ_0043314, and overexpression of Apelin 13 counteracted the influences of upregulation of miR-146b-3p in ovarian granulosa cells. Mechanically, circ_0043314 could bind to miR-146b-3p, and miR-146b-3p directly targeted and modulated Apelin 13 expression. LIMITATIONS: This study was limited by the lack of animal experiments. CONCLUSION: Our data demonstrated that circ_0043314 enhances ovarian granulosa cell proliferation and suppresses its apoptosis via miR-146b-3p/Apelin 13 axis.

Participation of the nitric oxide pathway in lordosis induced by apelin-13 in female rats.

The present study investigated the participation of the nitric oxide pathway in facilitating lordosis behavior induced by intrahypothalamic administration of apelin-13 in ovariectomized rats primed with estradiol benzoate (EB). The experiments involved the administration of a nitric oxide synthase inhibitor (L-NAME) or a nitric oxide-dependent, soluble guanylyl cyclase inhibitor (ODQ), and an inhibitor of protein kinase G (KT5823) to the ventromedial hypothalamus (VMH) of EB-primed rats 30 min before infusion of apelin-13 (0.75 µg/µl). This dose of apelin-13 consistently induces lordosis behavior at 30 min, 120 min, and 240 min following infusion. Results showed that injections of either L-NAME or KT5823 significantly reduced the lordosis induced by apelin at 120 and 240 min. However, VMH infusion of ODQ 30 min before apelin-13 infusion reduced but did not significantly inhibit, the lordosis elicited by this peptide at the same time points. We conclude that the nitric oxide pathway in the VMH plays an important role in lordosis induced by apelin-13 in EB-primed rats.

Neuroprotective Roles of Apelin-13 in Neurological Diseases.

Apelin is a natural ligand for the G protein-coupled receptor APJ, and the apelin/APJ system is widely distributed in vivo. Among the apelin family, apelin-13 is the major apelin isoform in the central nervous system and cardiovascular system, and is involved in the regulation of various physiopathological mechanisms such as apoptosis, neuroinflammation, angiogenesis, and oxidative stress. Apelin is currently being extensively studied in the nervous system, and apelin-13 has been shown to be associated with the onset and progression of a variety of neurological disorders, including stroke, neurodegenerative diseases, epilepsy, spinal cord injury (SCI), and psychiatric diseases. This study summarizes the pathophysiological roles of apelin-13 in the development and progression of neurological related diseases.

Apelin-13 Improves Cognitive Impairment and Repairs Hippocampal Neuronal Damage by Activating PGC-1α/PPARγ Signaling.

Alzheimer's disease (AD) is a complex neurodegenerative disease that is prevalent around the world. Both Apelin-13 and proliferator-activated receptor-γ (PPARγ)/PPARγ co-activator 1α (PGC-1α) are regarded as candidate targets for treating AD. The investigation examined whether Apelin-13 exerts neuroprotective effects via PGC-1α/PPARγ signaling. In this study, Apelin-13 improved cognitive deficits in AD mice, while SR-18,292 (a PGC-1α inhibitor) interfered with the therapeutic effects of Apelin-13. Mechanistically, Apelin-13, PGC-1α and PPARγ were decreased in AD mice and oxygen-glucose deprivation (OGD)-induced neuronal cells. Apelin-13 bound to PGC-1α and negatively regulated the expression of PGC-1α and PPARγ. In turn, PGC-1α accelerated the accumulation of Apelin-13 and PPARγ. Additionally, neuronal apoptosis was inhibited, and the abundance of apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase 3) was induced. The content of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) fluctuated. The level of inflammatory factors (interleukin-6, IL-6, IL-10, tumor necrosis factor-α, TNF-α) was regulated. In short, Apelin-13 exerted anti-apoptosis, anti-oxidant stress and anti-inflammatory effects. Interestingly, PGC-1α silencing promoted neuronal apoptosis, oxidant stress and inflammation, and overexpression of PGC-1α exhibited the opposite. More importantly, inhibition of PGC-1α attenuated Apelin-13-enhanced cognitive impairment and neuronal damage. Therefore, our findings suggested that Apelin-13 exerted neuroprotective effects in part via the PGC-1α/PPARγ pathway.

Apelin-13 protects against cisplatin-induced ototoxicity by inhibiting apoptosis and regulating STAT1 and STAT3.

The ototoxic side effect of cisplatin is a main cause of sensorineural hearing loss. This side effect limits the clinical application of cisplatin and affects patients' quality of life. This study was designed to investigate the effect of apelin-13 on cisplatin-induced C57BL/6 mice hearing loss model and explore the potential underlying molecular mechanisms. Mice were intraperitoneally injected with 100 µg/kg apelin-13 2 h before 3 mg/kg cisplatin injection for 7 consecutive days. Cochlear explants cultured in vitro were pretreated with 10 nM apelin-13 2 h prior to 30 µM cisplatin treatment for another 24 h. Hearing test and morphology results showed that apelin-13 attenuated cisplatin-induced mice hearing loss and protected cochlear hair cells and spiral ganglion neurons from damage. In vivo and in vitro experimental results showed that apelin-3 reduced cisplatin-induced apoptosis of hair cells and spiral ganglion neurons. In addition, apelin-3 preserved mitochondrial membrane potential and inhibited ROS production in cultured cochlear explants. Mechanistic studies showed that apelin-3 decreased cisplatin-induced cleaved caspase 3 expression but increased Bcl-2; inhibited the expression of pro-inflammatory factors TNF-a and IL-6; and increased STAT1 phosphorylation but decreased STAT3 phosphorylation. In conclusion, our results indicate that apelin-13 could be a potential otoprotective agent to prevent cisplatin-induced ototoxicity by inhibiting apoptosis, ROS production, TNF-α and IL-6 expression, and regulating phosphorylation of STAT1 and STAT3 transcription factors.

A prospective cohort study on decreased serum apelin-13 levels after human aneurysmal subarachnoid hemorrhage: associations with severity and prognosis.

Apelin-13 may have neuroprotective effects. We aimed to determine whether serum apelin-13 could serve as a potential biomarker for severity, delayed cerebral ischemia (DCI), and prognosis after human aneurysmal subarachnoid hemorrhage (aSAH). In this prospective, observational, cohort, single-center study of 139 patients with aSAH and 139 healthy individuals, serum apelin-13 levels were determined. The indicators of stroke severity were the Hunt-Hess scale and the modified Fisher grading scale. The prognostic parameters were DCI and 6-month worse prognosis (Extended Glasgow Outcome Scale scores of 1-4). Using binary logistic regression analysis, the relationship between serum apelin-13 levels and prognosis was reported as odds ratios (ORs) with 95% confidence intervals (CIs). Under the receiver operating characteristic curve, prognostic abilities were shown as areas under the curve (AUCs) with 95% CIs. Serum apelin-13 levels were substantially lower in patients than in controls (median, 28.8 versus 48.6 ng/ml; P < 0.001), in patients with DCI than in non-DCI patients (median, 14.9 versus 31.6 ng/ml; P < 0.001), and in patients with worse prognosis than in those with good prognosis (median, 16.3 versus 33.7 ng/ml; P < 0.001). Serum apelin-13 levels were independently correlated with Hunt-Hess scores (beta, -6.836; 95% CI, -8.963-4.708; VIF, 2.219; P = 0.001) and modified Fisher scores (beta, -3.350; 95% CI, -6.151-0.549; VIF, 1.562; P = 0.019). Serum apelin-13 levels were an independent predictor of DCI (OR, 0.951; 95% CI, 0.914-0.990; P = 0.022) and worse prognosis (OR, 0.954; 95% CI, 0.916-0.993; P = 0.013). Serum apelin-13 levels significantly differentiated DCI and poor prognosis, with AUCs of 0.753 (95% CI, 0.656-0.850) and 0.791 (95% CI, 0.713-0.868) respectively. Using the Youden method, serum apelin-13 levels < 19.3 ng/ml distinguished the risk of DCI with 64.7% sensitivity and 77.1% specificity, and serum apelin-13 levels < 30.2 ng/ml discriminated the development of worse prognosis with 89.1% sensitivity and 63.4% specificity. Serum apelin-13 levels combined with Hunt-Hess scores and modified Fisher scores displayed a significantly higher AUC than any one of them for prognostic prediction (all P < 0.05). Decreased serum apelin-13 levels, which are strongly correlated with disease severity, independently predicted poor outcomes following aSAH, substantializing serum apelin-13 as a useful prognostic biomarker of aSAH.

The effects of apelin-13 against cisplatin-induced nephrotoxicity in rats.

Acute kidney injury (AKI) is observed in nearly 60% of patients undergoing cisplatin (CP) therapy. The aim of this study was to reveal the potential effects of apelin-13 (AP-13) in the prevention of CP-induced renal toxicity, together with its antioxidant and anti-inflammatory effect mechanisms. Four experimental groups were established. Group 1, the control group, received 0.9% saline solution alone intraperitoneally (IP). Group 2, the CP group, received CP IP at 5 mg/kg once weekly for four weeks for induction of nephrotoxicity. In Group 3, the CP + Apelin-13 (AP-13) group, AP-13 was prepared at 20 nmol kg/d in sterile pyrogen-free saline before injection every day for four weeks and administered IP. CP was administered IP at 5 mg/kg once weekly for four weeks for induction of nephrotoxicity. In Group 4, the AP-13 group, AP-13 was prepared at 20 nmol kg/d in sterile pyrogen-free 0.9% saline before injection every day for four weeks and administered IP. Thiobarbituric acid reactive substances (TBARS), thiol (-SH), interleukin-1 beta, cleaved caspase-3, 8-hydroxy 2-deoxyguanosine (8-OHdG), and nuclear factor kappa B (NF-κß/p65) levels were then measured. Increased oxidative stress, inflammation, and apoptosis as a result of CP application activated the cascade. However, AP-13 administration reduced the oxidative stress increased by CIS with the determined antioxidant effect and reduced the damage by increasing total -SH levels. 8-OHdG and NF-κß/p65, which were up-regulated by triggering oxidative stress and inflammation, were down-regulated through the antioxidant and anti-inflammatory effects of AP-13.

Apelin-13 alleviates contrast-induced acute kidney injury by inhibiting endoplasmic reticulum stress.

Contrast-induced acute kidney injury (CI-AKI) is a severe complication associated with significant morbidity and mortality, and effective therapeutic strategies are still lacking. Apelin is an endogenous physiological regulator with antioxidative, anti-inflammatory and antiapoptotic properties. However, the role of apelin-13 in CI-AKI remains unclear. In our study, we found that the protein expression levels of apelin were significantly downregulated in rat kidney tissues and HK-2 cells during contrast media treatment. Moreover, we explored the protective effect of apelin-13 on renal tubule damage using in vitro and in vivo models of CI-AKI. Exogenous apelin-13 ameliorated endoplasmic reticulum stress, reactive oxygen species and apoptosis protein expression in contrast media-treated cells and rat kidney tissues. Mechanistically, the downregulation of endoplasmic reticulum stress contributed critically to the antiapoptotic effect of apelin-13. Collectively, our findings reveal the inherent mechanisms by which apelin-13 regulates CI-AKI and provide a prospective target for the prevention of CI-AKI.

Preliminary study on a novel biological scaffold loaded with Apelin-13 sustained-release microcapsules for promoting fallopian tube recanalization in rabbits. / è½½Apelin-13ç¼“é‡Šå¾®å›Šçš„æ–°åž‹ç”Ÿç‰©æ”¯æž¶ä¿ƒå ”è¾“åµç®¡å†é€šçš„åˆæ­¥ç ”ç©¶.

OBJECTIVES: Tubal factor infertility severely impairs the natural fertility of women, and there is for genuine tubal recanalization, including restoration of both the anatomy and function of the diseased fallopian tubes. Currently, there is no effective treatment available. This study aims to explore methods for promoting the repair and recanalization of fallopian tubes from these 2 aspects. METHODS: Apelin-13 sustained-release microspheres and poly (lactic-co-glycolic acid) (PLGA) three-dimensional (3D) biodegradable scaffolds were prepared. The basic characteristics and in vivo degradation (mass loss rate) of the biodegradable scaffolds were tested, along with the in vitro drug release (cumulative release rate), the in vivo drug release (Apelin-13 plasma concentration), and in vitro degradation (degradation rate) of the microspheres. The Apelin-13 microspheres (microsphere group)/PLGA 3D scaffolds loaded with Apelin-13 sustained-release microspheres (scaffold-microcapsule group) were injected/placed into the fallopian tubes of New Zealand rabbit of chronic salpingitis models. The patency, microscopic structure, and positive expression of estrogen receptor and progesterone receptor of the fallopian tubes in the control group, the model group, the microcapsule group, and the scaffold-microcapsule group was observed and compared. RESULTS: At the 4th week post-operation, the mass loss rate of the PLGA 3D scaffolds, the degradation rate of the microspheres, and the Apelin-13 sustained-release microspheres-generated cumulative release rate in vitro over 30 days were 98.66%, 70.58%, and 98.68% respectively. The plasma concentration of Apelin-13 reached its peak within 5 days and remained stable for 25 days. Compared with the model and microsphere groups, the scaffold-microsphere group showed a milder inflammatory reaction within the tubal lumen, a higher rate of fallopian tube patency, and higher expression levels of estrogen and progesterone receptors (all P<0.05). The indicators of the scaffold-microsphere group were close to those of the control group. CONCLUSIONS: The PLGA 3D scaffolds loaded with Apelin-13 sustained-release microspheres can comprehensively repair the anatomical structure and physiological function of the fallopian tubes and hold promise for truly effective tubal recanalization.

Apelin-13/APJ induces cardiomyocyte hypertrophy by activating the Pannexin-1/P2X7 axis and FAM134B-dependent reticulophagy.

Cardiac hypertrophy is a leading cause of cardiac morbidity and mortality worldwide. Apelin is the endogenous ligand for the G protein-coupled receptor, APJ. Previously, we have revealed that apelin-13 can induce cardiomyocyte hypertrophy by activating the autophagy pathway. However, the precise mechanism through which apelin-13 regulates reticulophagy to participate in cardiomyocyte hypertrophy remains unclear. Herein, we observed that apelin-13-induced cardiomyocyte hypertrophy by activating FAM134B-dependent reticulophagy via the Pannexin-1/P2X7 signal pathway. Furthermore, we found that apelin-13 stimulated the opening of Pannexin-1 hemichannel and increased extracellular ATP (eATP) levels, which activated the P2X7 purinergic receptor. Activation of the Pannexin-1/eATP/P2X7 axis subsequently led to FAM134B-dependent reticulophagy. Moreover, inhibition of the Pannexin-1/P2X7 axis and FAM134B-dependent reticulophagy reversed apelin-13-induced cardiomyocyte hypertrophy. Based on our present findings, apelin-13/APJ induces cardiomyocyte hypertrophy by activating the Pannexin-1/P2X7 axis and FAM134B-dependent reticulophagy.

Research Progress on Mechanism of Neuroprotective Roles of Apelin-13 in Prevention and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia. Currently, more than 50 million people live with dementia worldwide, and this number is expected to increase. Some of the typical pathological changes of AD include amyloid plaque, hyperphosphorylation of tau protein, secretion of inflammatory mediators, and neuronal apoptosis. Apelin is a neuroprotective peptide that is widely expressed in the body. Among members of apelin family, apelin-13 is the most abundant with a high neuroprotective function. Apelin-13/angiotensin domain type 1 receptor-associated proteins (APJ) system regulates several physiological and pathophysiological cell activities, such as apoptosis, autophagy, synaptic plasticity, and neuroinflammation. It has also been shown to prevent AD development. This article reviews the research progress on the relationship between apelin-13 and AD to provide new ideas for prevention and treatment of AD.

Apelin-13 attenuates early brain injury through inhibiting inflammation and apoptosis in rats after experimental subarachnoid hemorrhage.

BACKGROUND: Early brain injury (EBI) has been considered as the major contributor to the neurological dysfunction and poor clinical outcomes of subarachnoid hemorrhage (SAH). Studies showed that apelin-13 exhibits a neuroprotective effect in brain damage induced by cerebral ischemia. However, it remains unclear whether apelin-13 could exhibit the protective functions following SAH. The present study aimed to validate the neuroprotective role of apelin-13 in SAH, and further investigated the underlying mechanisms. METHODS AND RESULTS: We constructed SAH rat model and we found that apelin-13 significantly alleviated neurological disorder and brain edema, improved memory deficits in SAH rats. Apelin-13 treatment decreased contents of TNF-α and IL-1ß in cerebral spinal fluid of SAH rat by using ELISA. Apelin-13 treatment promoted the expression of APJ and Bcl-2, and decreased the level of active caspase-3 and Bax in the temporal cortex after SAH by using western blot. Also, apelin-13 attenuated the cortical cell death and neuronal degeneration as shown by TUNEL, FJB and Nissl staining. However, ML221, an inhibitor of APJ, significantly reversed all the above neuroprotective effects of apelin-13. Moreover, a neuron-microglia co-culture system, which mimic SAH in vitro, confirmed the protective effect of apelin-13 on neurons and the inhibitory effect on inflammation through apoptosis-related proteins. CONCLUSIONS: These data demonstrated that apelin-13 exhibit a neuroprotective role after SAH through inhibition of apoptosis in an APJ dependent manner.

Apelin receptor homodimer inhibits apoptosis in vascular dementia.

Apelin receptor (APJ), a member of family A of the G protein-coupled receptors (GPCRs), is a potential pharmaceutical target for diseases of the nervous system. Our previous work revealed that human APJ can form a homodimer that has different functional characteristics than the monomer. To investigate the effects of APJ homodimers on neuroprotection in vascular dementia (VD), we established VD model in rats and treated the animals by injecting apelin-13 into the lateral ventricle. In addition, we established an oxygen-glucose deprivation/reoxygenation (OGD/R) model in SH-SY5Y cells treated with apelin-13. After apelin-13 stimulation in the VD rat, the level of APJ and APJ homodimer were elevated. Furthermore, APJ homodimer decreased the level of cleaved caspase-3 and cleaved caspase-9 via the Gαi3 and Gαq signaling pathway, thereby increasing the number of neurons and inhibiting apoptosis. Consequently, APJ homodimers may serve as a unique mechanism for neuroprotection against VD and provide new pharmaceutical targets for VD.

The protective effect of apelin-13 on cardiorenal toxicity induced by cyclophosphamide.

Cyclophosphamide is a chemotherapeutic drug that is widely used in the clinic and can cause multi-organ toxicity. Apelin-13 is an endogenous adipocytokine with antioxidant properties. Therefore, this study investigated the possibility of apelin-13 being a potential therapeutic agent on cardiac toxicity and nephrotoxicity caused by cyclophosphamide. In this study, a total of four groups were formed with eight rats in each group. Group I: the control group was administered only saline (i.p.). Group II: cyclophosphamide, a single dose of 200 mg/kg (i.p.) on day 7. Group III: apelin-13 (15 µg/kg), for 7 days (i.p.). Group IV: administered apelin-13 (15 µg/kg) (i.p.) for 7 days and a single dose of cyclophosphamide (200 mg/kg) (i.p.) on day 7, the rats were sacrificed on day 8. Lactate dehydrogenase, cardiac troponin I (cTnI), creatine kinase MB (CK-MB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), malondialdehyde, creatinine, and blood urea nitrogen were found to be high in the cyclophosphamide group; however, these values were reduced with apelin-13 administration. Antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and reduced glutathione (GSH) decreased in the cyclophosphamide group, and apelin-13 increased these enzyme activities. In addition, histopathological examinations also supported the results obtained. The findings of this study showed that apelin-13 has a protective effect against cardiorenal toxicity caused by cyclophosphamide.

Correlation between apelin and VEGF levels in retinopathy of prematurity: a matched case-control study.

BACKGROUND: Although several clinical studies have analysed the relationship between the levels of vascular endothelial growth factor (VEGF) and apelin-13 in venous blood and retinopathy of prematurity (ROP), no definitive conclusions have been reached. This study aimed to investigate the relationship between apelin-13 levels and VEGF levels and ROP. METHODS: Differences in plasma apelin-13 and VEGF levels were analysed in two groups of infants born with birth weight < 1500 g and gestational age < 32 weeks at Peking University People' s Hospital. One group comprised infants diagnosed with ROP and the other group was a control group comprising infants without ROP. RESULTS: Apelin-13 levels were significantly lower in the ROP group than in the control group, while VEGF levels showed the opposite result (both P < 0.001). Infants with severe ROP had lower apelin-13 levels and higher VEGF levels than with mild ROP (both P < 0.05).The receiver operating characteristic curve for apelin-13 level as the indicator of ROP showed that a cut-off value of 119.6 pg/mL yielded a sensitivity of 84.8% and a specificity of 63.6%, while for VEGF level, the cut-off value of 84.3 pg/mL exhibited a sensitivity of 84.8% and a specificity of 66.7%. CONCLUSIONS: Plasma apelin-13 and VEGF levels at 4-6 weeks of age may play a role in assisting the diagnosis of ROP.

Apelin-13 protects against memory impairment and neuronal loss, Induced by Scopolamine in male rats.

The present study aimed to evaluate the effects of Apelin-13 on scopolamine-induced memory impairment in rats. Forty male rats were divided into five groups of eight. The control group received no intervention; the scopolamine group underwent stereotaxic surgery and received 3 mg/kg intraperitoneal scopolamine. The treatment groups additionally received 1.25, 2.5 and 5 µg apelin-13 in right lateral ventricles for 7 days. All rats (except the control group) were tested for the passive avoidance reaction, 24 h after the last drug injection. For histological analysis, hippocampal sections were stained with cresyl violet; synaptogenesis biochemical markers were determined by immunoblotting. Apelin-13 alleviated scopolamine-induced passive avoidance memory impairment and neuronal loss in the rats' hippocampus (P<0.001). The reduction observed in mean concentrations of hippocampal synaptic proteins (including neurexin1, neuroligin, and postsynaptic density protein 95) in scopolamine-treated animals was attenuated by apelin-13 treatment. The results demonstrated that apelin-13 can protect against passive avoidance memory deficiency, and neuronal loss, induced by scopolamine in male rats. Further experimental and clinical studies are required to confirm its therapeutic potential in neurodegenerative diseases.