Role Of Apelin Research Articles

The Role of Apelin and Protamine Sulfate in Bile Duct Ligation-Induced Liver Fibrosis in Rats

The Role of Apelin and Protamine Sulfate in Bile Duct Ligation-Induced Liver Fibrosis in Rats

Protamine as a barrier against the angiogenic effect of insulin: a possible role of apelin

Insulin is proved to have angiogenic ability thereby may worsen the diabetic retinopathy (DR) progression. Insulin also triggers the expression of endogenous angiogenic peptide, apelin. Since protamine was introduced as an inhibitor of the apelin receptor, we hypothesized that use of protaminated insulin instead of non-protaminated insulin can decrease the negative role of insulin in progression of DR. Firstly, the incidence of DR was compared among three diabetic patient groups: an oral medication, non-protaminated insulin, and protaminated insulin (PIns). Proliferation and migration rate of HUVECs was measured after insulin, apelin, and protamine exposure. In clinical study, the chance of developing DR was 8.5 and 4.1 times higher in insulin group and PIns groups compared with oral group respectively. Insulin group had a chance of 9.5-folds of non-proliferative DR compared to oral group. However, the difference of non-proliferative DR between PIns and oral group wasn’t significant. In-vitro tests showed that concomitant use of insulin and apelin increases viability and migratory potential of HUVECs. However, protamine could reverse this effect. Protamine present in some insulins might show a promising protective role against diabetic retinopathy. Thus, protaminated insulins may be preferable in the treatment of diabetes.

Effect of Apelin on Hepatic Dysfunction in a Rat Model of Heart Failure

Background Severe heart failure can be accompanied with liver dysfunction. The role of apelin in liver disease is still a matter of debate. The aim of this study is to examine the effect of apelin on liver dysfunction in heart failure rat model and the underlying mechanisms of this effect. Materials and Methods 39 female Wistar rats were divided into three groups 13 each; control (Intraperitoneal saline for 2 weeks, daily), Isoprenaline (ISO) (Intraperitoneal saline for 2 weeks, ISO in the last 2 days (100 mg/kg, subcutaneous) and Apelin group (apelin, 15 µg/kg/day Intraperitoneal for 2 weeks and ISO in the last 2 days). Body weights, heart and liver weights, ECG record, isolated heart study and histopathological examination for both heart and liver were carried out. Serum cardiac troponin T (cTnT), liver enzymes (alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH) and apelin and liver APJ receptors, malondialdehyde (MDA), reactive oxygen species (ROS) and cytochrome C were measured. Results Apelin decreased heart weights, shortened QRS complex as well as observed and corrected Q-T intervals, increased R voltage, peak developed tension, peak developed tension per left ventricular weights and mean coronary flow rate compared to ISO treated rats. It decreased serum levels of cTnT, ALT, AST& LDH and improved serum apelin level. Also, it enhanced the hepatic expression of APJ receptor and decreased MDA & ROS and cytochrome C in liver tissue. Conclusion Apelin had a protective role against hepatic dysfunction that accompanied heart failure through its antioxidant and anti-apoptotic effects.

Apelin Prevents and Alleviates Crystalline Silica-induced Pulmonary Fibrosis via Inhibiting Transforming Growth Factor Beta 1-triggered Fibroblast Activation.

Silicosis is a common and ultimately fatal occupational disease, yet the limited therapeutic option remains the major clinical challenge. Apelin, an endogenous ligand of the G-protein-coupled receptor (APJ), is abundantly expressed in diverse organs. The apelin-APJ axis helps to control pathological and physiological processes in lung. The role of apelin in the pathological process and its possible therapeutic effects on silicosis have not been elucidated. In this study, we found that lung expression and circulating levels of apelin were markedly decreased in silicosis patients and silica-induced fibrotic mice and associated with the severity. Furthermore, in vivo data demonstrated that pre-treatment from day 3 and post-treatment from day 15 with apelin could both alleviate silica-induced pulmonary fibrosis in mice. Besides, apelin inhibited pulmonary fibroblast activation via transforming growth factor beta 1 (TGF-β1) signaling. Our study suggested that apelin could prevent and reverse silica-induced pulmonary fibrosis by inhibiting the fibroblast activation through TGF-β1 signaling pathway, thus providing a new potential therapeutic strategy for silicosis and other pulmonary fibrosis.

Apelin alleviated neuroinflammation and promoted endogenous neural stem cell proliferation and differentiation after spinal cord injury in rats

BackgroundSpinal cord injury (SCI) causes devastating neurological damage, including secondary injuries dominated by neuroinflammation. The role of Apelin, an endogenous ligand that binds the G protein-coupled receptor angiotensin-like receptor 1, in SCI remains unclear. Thus, our aim was to investigate the effects of Apelin in inflammatory responses and activation of endogenous neural stem cells (NSCs) after SCI.MethodsApelin expression was detected in normal and injured rats, and roles of Apelin in primary NSCs were examined. In addition, we used induced pluripotent stem cells (iPSCs) as a carrier to prolong the effective duration of Apelin and evaluate its effects in a rat model of SCI.ResultsCo-immunofluorescence staining suggested that Apelin was expressed in both astrocytes, neurons and microglia. Following SCI, Apelin expression decreased from 1 to 14 d and re-upregulated at 28 d. In vitro, Apelin promoted NSCs proliferation and differentiation into neurons. In vivo, lentiviral-transfected iPSCs were used as a carrier to prolong the effective duration of Apelin. Transplantation of transfected iPSCs in situ immediately after SCI reduced polarization of M1 microglia and A1 astrocytes, facilitated recovery of motor function, and promoted the proliferation and differentiation of endogenous NSCs in rats.ConclusionApelin alleviated neuroinflammation and promoted the proliferation and differentiation of endogenous NSCs after SCI, suggesting that it might be a promising target for treatment of SCI.

Role of Apelin, Adipsin and C-reactive protein in patients with chronic kidney disease

Chronic kidney disease (CKD) is a growing global health problem. The adipose tissue may directly affect the kidney through its activity as an endocrine gland through the secretion of adipokines. This study was a cross sectional which conducted in Kirkuk city for the period from June 2020 to September 2021.study population age ranged from (30 – 90) years old. The total of 80 subjects was separated to two groups as following: Kidney failure group: 65 patients and control group: 15 patients. The results referred to the increased levels of Apelin, Adipsin and C reactive protein (CRP) in CKD with highly significant differences (P≤0.01) when compared with control group, also a positive correlation was found between Adipsin and Apelin in the second stage (r = 0.742) , the third stage (r = 0.573) and in the fifth stage (r = 0.552).

Low serum apelin levels are associated with mild cognitive impairment in Type 2 diabetic patients

BackgroundApelin is a new adipokine that is secreted by adipocytes, and is associated with insulin resistance (IR), inflammation, and obesity. This study was designed to investigate the role of apelin in type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI).MethodsA total of 235 patients with T2DM were included. The cognitive function of patients was evaluated using Montreal Cognitive Assessment (MoCA) tool, then patients were divided into MCI group and non-MCI group according to the MoCA score. Blood sample was analyzed for the level of apelin by enzyme-linked immunosorbent assay (ELISA).ResultsThe MCI group (n = 73) presented lower serum apelin levels compared with the patients with normal cognitive function (P < 0.001). Apelin levels showed significantly negative correlation with diabetes duration, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C, creatinine and high sensitivity C-reactive protein (hs-CRP), and positive correlation with high-density lipoprotein cholesterol (HDL-C) and brain-derived neurotrophic factor (BDNF). Multivariable logistic regression analysis indicated that serum apelin (OR = 0.304, 95%CI: 0.104–0.886, P = 0.029), as well as education levels, diabetes duration, cardiovascular disease, serum HbA1c, HDL-C, creatinine, and BDNF, were independent risk factors of MCI in patients with T2DM.ConclusionsSerum apelin level is reduced in T2DM patients with MCI. Apelin might has protective effect against cognitive impairment and serve as a serum biomarker of T2DM.

Apelin Resistance Contributes to Muscle Loss during Cancer Cachexia in Mice.

Simple SummaryCancer cachexia is a highly debilitating syndrome involving severe body weight loss. Worldwide around 9–14.5 million cancer patients suffer from cachexia every year and many of them die because of cachexia. Our study aimed to assess the possible role of apelin against muscle loss during cancer growth given its beneficial effects against muscle atrophy during aging. We found apelin exhibiting advantageous effects against atrophy in in vitro models, but not in in vivo models, where we unraveled undesirable apelin resistance that may nullify apelin-based therapy for cancer cachexia.Cancer cachexia consists of dramatic body weight loss with rapid muscle depletion due to imbalanced protein homeostasis. We found that the mRNA levels of apelin decrease in muscles from cachectic hepatoma-bearing rats and three mouse models of cachexia. Furthermore, apelin expression inversely correlates with MuRF1 in muscle biopsies from cancer patients. To shed light on the possible role of apelin in cachexia in vivo, we generated apelin 13 carrying all the last 13 amino acids of apelin in D isomers, ultimately extending plasma stability. Notably, apelin D-peptides alter cAMP-based signaling in vitro as the L-peptides, supporting receptor binding. In vitro apelin 13 protects myotube diameter from dexamethasone-induced atrophy, restrains rates of degradation of long-lived proteins and MuRF1 expression, but fails to protect mice from atrophy. D-apelin 13 given intraperitoneally for 13 days in colon adenocarcinoma C26-bearing mice does not reduce catabolic pathways in muscles, as it does in vitro. Puzzlingly, the levels of circulating apelin seemingly deriving from cachexia-inducing tumors, increase in murine plasma during cachexia. Muscle electroporation of a plasmid expressing its receptor APJ, unlike apelin, preserves myofiber area from C26-induced atrophy, supporting apelin resistance in vivo. Altogether, we believe that during cachexia apelin resistance occurs, contributing to muscle wasting and nullifying any possible peptide-based treatment.

Apelin is associated with clinicopathological parameters and prognosis in breast cancer patients.

Apelin has been shown to be a novel angiogenic factor in various cancers. However, there is limited information regarding the role of apelin in breast cancer. The aim of the present study is to examine associations between apelin, clinicopathological variables, and clinical outcome in breast cancer patients. In this study, we began by investigating the apelin expression in breast cancer with long-term follow-up using immunohistochemistry. We then analyzed the relationship between apelin expression and microvessel density (MVD), lymphatic vessel density (LVD), lymph node status as well as other established clinicopathological parameters. The relationship between apelin expression and prognosis was also studied. In addition, we compared the apelin and its ligant APJ expression between 30 breast cancer samples and normal breast tissues adjacent to the breast tumors using western blot (WB) and RT-PCR. Apelin protein expression was detected in the cytoplasm of the breast carcinoma cells at various intensities. Apelin expression was positive in 59.2% (84/142) of the breast cancer patients and apelin expression was significantly correlated with tumor size (p = 0.030), stage (p = 0.000), histological type (p = 0.009), MVD (p = 0.000), LVD (p = 0.000), and lymph node metastasis (p = 0.041). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that high expression of apelin was associated with both worse disease-free survival (p < 0.001) and overall survival (p < 0.001). Interestingly, a significant difference in apelin and APJ expression by WB as well as RT-PCR was observed between normal breast tissues adjacent to the breast tumors and breast cancer tissues. Our results showed apelin expression was associated with tumor size, stage, histological type, MVD, LVD, lymph node metastasis and poor prognosis. The presence of apelin may be a new prognostic factor and potential therapeutic target for breast cancer.

The Role of Apelin in Obesity Treatment by Exercise Training

The Role of Apelin in Obesity Treatment by Exercise Training

The Possible Role of Apelin and Adiponectin in Multiple Sclerosis Pathogenesis

Introduction: Adipocytokines are described as molecules synthesized from adipocytes, and in addition to their roles in metabolic disorders, these cytokines have recently been the focus of interest in autoimmune diseases. In this comparative study, we aimed to determine the levels of apelin and adiponectin molecules between relapses/remissions of MS and control subjects. Methods: In this study, we include 34 relapsing-remitting MS (RRMS) patients and 20 healthy controls to evaluate apelin and adiponectin serum levels via the Enzyme-linked immunosorbent assay method. Results: Between the RRMS and control groups, these molecule levels were statistically insignificant. On the other hand, significant differences were noted in terms of apelin and adiponectin levels between genders. Discussion and Conclusion: Adipocytokines such as adiponectin, leptin, visfatin, adipsin, apelin, and ghrelin have already been examined in neuroinflammatory and neurodegenerative conditions. Despite the limited features of our study, the measured difference between apelin and adiponectin, especially during relapse, suggests that it may be possibly involved in this pathogenesis. Moreover, a significant difference was noted between serum adiponectin, apelin levels, and sex. We found higher levels in females compared to males in the remission period. The reason for this situation is yet to be identified, but we assumed that this may be attributed to the difference between fatty acid metabolism in men and women. In addition, this result correlates with the theoretical fact that MS affects women three times more often than men, and the prognosis in women is generally better than in men, which raises curiosity about the possible neuroprotective role of these molecules.

The Possible Role of Apelin and Sirtuin 1 in Migraine Pathogenesis

The Possible Role of Apelin and Sirtuin 1 in Migraine Pathogenesis

The Role of Apelin and Apelin Receptor Expression in Migration and Invasiveness of Colon Cancer Cells.

Colon cancer is the second deadliest malignancy for human. Its correlation with obesity has led to an increasing number of studies focusing on the role of adipokines in colon cancer development. Apelin, which belongs to the family of adipokines, affects several pathological processes, including heart diseases, obesity and carcinogenesis. In this study, we examined the importance of apelin and apelin receptor (APJ) during motility regulation of colon cancer cells. Colon cancer cells with overexpression of apelin receptor, as well as cells with down-regulation of apelin were used in this study. Migration and invasion ability was tested using Transwell® filters. The proteolytic activity was analyzed with fluorescent-substrate degradation assay and gelatin zymography. We also used confocal microscopy to examine migratory protrusion formation and the localization of MT1-MMP. The levels of AKT and ERK kinases were evaluated using Western blotting assay. Overexpression of APJ receptor resulted in increased migration and invasion abilities through stimulation of migratory protrusion formation and proteolytic activity. These processes were mediated by PI3K/AKT and MAPK signaling pathways. Opposite effect was obtained when the level of apelin was down-regulated. The level of apelin and its receptor is strictly connected with regulation of migration and invasion of colon cancer cells. Therefore, apelinergic system seems to be a promising target for anti-cancer therapy.

Abstract 16473: Loss of the Apelin-Apelin Receptor Signaling Axis Worsens Hemodynamic Alterations and Right Ventricular (rv) Adaptation and Abrogates 17ß-Estradiol (E2)-Mediated Protection in Experimental Pulmonary Arterial Hypertension (PAH)

Introduction: Women are more likely to develop PAH but exhibit more favorable hemodynamics and better survival than men. These improved outcomes have been linked to protective effects of E2. We recently linked RV-protective effects of E2 to regulation of apelin signaling. However, the role of apelin and its receptor APJ in RV failure is unknown. Hypothesis: RV cardiomyocytes (RVCM)-derived apelin exerts beneficial effects on RV endothelial cells (RVECs). Apelin-APJ signaling is necessary for E2’s RV-protective effects. Methods: Apelin and APJ abundance were quantified (Western blot) and immunolocalized in RVs from PAH patients. In vivo , RV failure was induced in male Sprague-Dawley rats by pulmonary artery banding (PAB). A subset of PAB rats were treated with E2 ± APJ inhibitor ML221. Hemodynamics, RV function and molecular changes were assessed. To study the role of RVCM apelin, conditioned media was collected from RVCMs after apelin knockdown and then added to RVECs. In addition, conditioned media from untreated RVCMs was added to RVECs pretreated with ML221. Lastly, RVECs were treated with E2 ± siApelin or ML221. p&lt;0.05 was considered statistically significant. Results: In PAH RVs, apelin and APJ localized to RVCMs and RVECs and were decreased vs controls (p&lt;0.05). In PAB+E2+ML221 rats, inhibition of apelin signaling resulted in more RV hypertrophy and decreased RV function (p&lt;0.05 vs sham or PAB+E2). Conditioned media from RVCMs+siApelin reduced RVEC eNOS phosphorylation, transwell migration and ring formation (p&lt;0.05 vs scrambled control conditioned media). Concomitantly, treatment of RVECs with ML221 blocked transwell migration and ring formation induced by RVCM conditioned media (p&lt;0.05 vs RVEC+veh control). Lastly, treatment of RVECs with siApelin or ML221 abrogated stimulatory effects of E2 on angiogenic function (p&lt;0.05). Conclusions: Apelin and APJ are decreased in PAH-RVs and loss of apelin-APJ signaling results in more severe RV failure and abrogates E2-mediated RV protection. Apelin is secreted by RVCMs and exerts a beneficial paracrine effect on RVECs, where it is required for E2 to stimulate angiogenesis. Apelin-APJ signaling may represent a novel and therapeutically targetable, cell- and sex-specific signaling axis in the RV.

Lack of association between circulating apelin level and frailty-related functional parameters in older adults: a cross-sectional study

BackgroundApelin, an active endogenous peptide, has been recently receiving great attention as a promising target for antiaging intervention, primarily based on results from genetically altered mice. To validate previous experimental data and investigate the possible role of apelin in humans, in this study, we examined serum apelin level in relation to frailty and its associated parameters in a cohort of ambulatory, community-dwelling older adults.MethodsBlood samples were collected from 80 participants who underwent a comprehensive geriatric assessment, and apelin level was measured using an enzyme immunoassay kit. Phenotypic frailty and deficit-accumulation frailty index (FI) were assessed using widely validated approaches, proposed by Fried and Rockwood groups, respectively.ResultsAfter adjustment for sex, age, and body mass index, serum apelin level was found to be not significantly different according to phenotypic frailty status (P = 0.550) and not associated with FI, grip strength, gait speed, time to complete 5 chair stands, and muscle mass (P = 0.433 to 0.982). To determine whether the association between serum apelin level and frailty has a threshold effect, we divided the participants into quartiles according to serum apelin level. However, there were no differences in terms of frailty-related parameters and the risk for frailty among the quartile groups (P = 0.248 to 0.741).ConclusionsThe serum apelin level was not associated with both phenotypic frailty and functional parameters in older adults, despite its beneficial effects against age-related physiologic decline in animal models. Further large-scale longitudinal studies are necessary to understand the definite role of circulating apelin in frailty risk assessment.

The evaluation of serum apelin levels in patients complicated with preeclampsia

Objective The aim of this study was to investigate the serum levels of mild, severe preeclamptic pregnants and normotensive pregnant women to determine whether there is a correlation between preeclampsia and their serum levels. Methods This prospective case-control study included 48 preeclamptic and 39 healthy normotensive pregnants. The control group was composed of body mass index and age matched pregnant women. Preeclamptic patients were divided into two groups as mild preeclampsia and severe preeclampsia. Serum apelin levels were determined by EnzymeImmunometricAssay (EIA) biochemical test. Results Serum apelin levels were found to be significantly lower in the preeclampsia group. It was 0.75 ± 0.24 ng/ml in mild preeclampsia and 0.55 ± 0.18 ng/ml in the severe preeclampsia and 0.91 ± 0.20 ng/ml in the control group. There was a strong inverse correlation between serum apelin levels and Systolic Blood Pressure (SBP) (r: −0.429 p: 0.002). Conclusions In conclusion, the role of apelin and apelinergic system in cardiovascular system and placental development and their place in preeclampsia is still an issue. In preeclampsia, the deterioration of the cardiovascular protective effect of apelin by other enzymes may also contribute to the deterioration of fetal development. More detailed studies are needed.

Intrathecally Administered Apelin-13 Alleviated Complete Freund’s Adjuvant-Induced Inflammatory Pain in Mice

Apelin is the endogenous ligand for APJ, a G-protein-coupled receptor. Apelin gene and protein are widely distributed in the central nervous system and peripheral tissues. The role of apelin in chronic inflammatory pain is still unclear. In the present study, a mouse model of complete Freund’s adjuvant (CFA)-induced inflammatory pain was utilized, and the paw withdrawal latency/threshold in response to thermal stimulation and Von Frey filament stimulation were recorded after intrathecal (i.t.) injection of apelin-13 (0.1, 1, and 10 nmol/mouse). The mRNA and protein expression, concentration of glutamic acid (Glu), and number of c-Fos immunol staining in lumbar spinal cord (L4/5) were determined. The results demonstrated that Apln gene expression in the lumbar spinal cord was down-regulated in the CFA pain model. Apelin-13 (10 nmol/mouse, i.t.) alleviated CFA-induced inflammatory pain, and it exhibited a more potent antinociceptive effect than apelin-36 and (pyr)apelin-13. The antinociception of apelin-13 could be blocked by APJ antagonist apelin-13(F13A). I.T. apelin-13 attenuated the increased levels of Aplnr, Grin2b, Camk2d, and c-Fos genes expression, Glu concentration, and NMDA receptor 2B (GluN2B) protein expression caused by CFA. Apelin-13 significantly reduced the number of Fos-positive cells in laminae III and IV/V of the dorsal horn. This study indicated that i.t. apelin-13 exerted an analgesic effect against inflammatory pain, which was mediated by activation of APJ, and inhibition of Glu/GluN2B function and neural activity of the spinal dorsal horn.

Glomerular endothelial cell heterogeneity in Alport syndrome

Glomerular endothelial cells (GEC) are a crucial component of the glomerular physiology and their damage contributes to the progression of chronic kidney diseases. How GEC affect the pathology of Alport syndrome (AS) however, is unclear. We characterized GEC from wild type (WT) and col4α5 knockout AS mice, a hereditary disorder characterized by progressive renal failure. We used endothelial-specific Tek-tdTomato reporter mice to isolate GEC by FACS and performed transcriptome analysis on them from WT and AS mice, followed by in vitro functional assays and confocal and intravital imaging studies. Biopsies from patients with chronic kidney disease, including AS were compared with our findings in mice. We identified two subpopulations of GEC (dimtdT and brighttdT) based on the fluorescence intensity of the TektdT signal. In AS mice, the brighttdT cell number increased and presented differential expression of endothelial markers compared to WT. RNA-seq analysis revealed differences in the immune and metabolic signaling pathways. In AS mice, dimtdT and brighttdT cells had different expression profiles of matrix-associated genes (Svep1, Itgβ6), metabolic activity (Apom, Pgc1α) and immune modulation (Apelin, Icam1) compared to WT mice. We confirmed a new pro-inflammatory role of Apelin in AS mice and in cultured human GEC. Gene modulations were identified comparable to the biopsies from patients with AS and focal segmental glomerulosclerosis, possibly indicating that the same mechanisms apply to humans. We report the presence of two GEC subpopulations that differ between AS and healthy mice or humans. This finding paves the way to a better understanding of the pathogenic role of GEC in AS progression and could lead to novel therapeutic targets.

Apelin and apj in common carp ( Cyprinus carpio L.): Molecular characterization, tissue expression and responses to periprandial changes and fasting–refeeding

Apelin and its receptor apj have a variety of biological functions and are involved in appetite and energy regulation. However, the comparative studies of apelin/apj system in fish are still absent. In this study, the open reading frames of apelin and apja and apjb were obtained. Apelin and apj mRNAs were widely distributed in all tissues detected, with the highest level in the brain, followed by the spleen, kidney and foregut. The mRNA expression of apelin and apjs increased rapidly at mealtime and significantly decreased after 30 min of feeding. In addition, there were obvious circadian rhythms (higher at nighttime and lower at daytime) in the expression of apelin and apja and apjb. Furthermore, fasting elevated the mRNA levels of apelin and apjs in the hypothalamus, foregut and hepatopancreas. When the 8-day fasted fish were refed, apelin and apjs mRNA expression significantly decreased. However, there were differences in the response to fasting and refeeding between apja and apjb. The roles of apelin and its receptor apjs in fish are poorly understood. Herein, we employed molecular and physiological studies to characterize their structures, distribution and mRNA expression responses to periprandial changes and fasting–refeeding in Cyprinus carpio L. for the first time.

Abstract 931: Compensatory Response of Perivascular Adipose Tissue to Vascular Dysfunction in Metabolic Syndrome Rats Involves Apelin

Perivascular adipose tissue (PVAT) regulates vascular homeostasis including vascular tone via release of adipokines. Using SHRSP.Z- Lepr fa /IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS), we have demonstrated that mesenteric PVAT enhances vasodilation under impaired vasodilation, in response to nitric oxide. We have also shown that the compensatory effect of PVAT disappears later in the course of MetS. Apelin is an adipokine that is produced at high levels in obesity and acts as a vasorelaxing factor. In this study, we evaluated the role of apelin in the enhancing effect of mesenteric PVAT on relaxations in SHRSP.ZF rats, by examining whether apelin canenhance vasorelaxation in the mesenteric arteries of SHRSP.ZF rats without PVAT, as it does in those with PVAT. Furthermore, we investigated whether apelin expression changes with increasing age. SHRSP.ZF rats at 17, 20, 23, and 30 weeks old were used. The mesenteric artery and surrounding adipose tissue were isolated from each rat; PVAT samples were isolated from surrounding adipose tissue; and the mRNA transcript level of apelin was examined by quantitative real-time PCR assays. Mesenteric arterial ring preparations with and without PVAT were made, and after a stable contraction was obtained by adding phenylephrine, relaxation was elicited using acetylcholine in the presence or absence of apelin (100 ng/mL, 20 min). There was no significant difference in apelin mRNA levels between 17 and 20 weeks, but there was a decrease at 23 and 30 weeks of age, which was when the enhancing effect of PVAT on vasodilation in SHRSP.ZF rats was impaired. In the presence of apelin, acetylcholine-induced relaxation in arteries without PVAT was significantly increased to the level of the response in arteries with PVAT in SHRSP.ZF rats at 20 weeks. These findings suggest that apelin is involved in the enhancing effect of PVAT in MetS rat mesenteric artery, and decreases in the level is associated with deterioration of PVAT function. Further study to investigate the mechanisms underlying the decrease in apelin production with increasing age in metabolic syndrome is needed, butthe apelin level could be one of the predictors for development of cardiovascular complications in patients with MetS.