Post-translational modifications of the apelin receptor regulate its functional expression.

Post-translational modifications (PTMs) are protein modifications that occur after protein biosynthesis, playing a crucial role in regulating protein function. They are involved in the functional expression of G-protein-coupled receptors (GPCRs), as well as intracellular and secretory protein signaling. Here, we aimed to investigate the PTMs of the apelin receptor (APLNR), a GPCR and their potential influence on the receptor's function. In an in vitro experiment using HEK cells, we only observed glycosylation as a PTM of the APLNR and ineffective receptor signaling by the agonist, (Pyr1)-apelin-13. In contrast, when analyzing mouse spinal cord, we detected glycosylation and other PTMs, excluding isopeptidation. This suggests that additional PTMs are involved in the functional expression of the APLNR in vitro. In summary, these findings suggest that the APLNR in vivo requires multiple PTMs for functional expression. To comprehensively understand the pharmacological effects of the APLNR, it is essential to establish an in vitro system that adequately replicates the receptor's PTM profile. Nonetheless, it is crucial to overcome the challenge of heat-sensitive proteolysis in APLNR studies. By elucidating the regulation of PTMs, further research has the potential to advance the analysis and pharmacological studies of both the apelin/APLNR system and GPCR signal modulation.

Apelin/Apelin receptor: A new therapeutic target in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is an endocrinopathy, and it accounts for 75% of non-ovulatory infertile in women of childbearing age. It is clear that obesity, insulin resistance, dyslipidaemia coexist in PCOS. Apelin, as an endogenous ligand of the previously orphan receptor, is an adipokine that secreted by adipose tissue. Apelin and apelin receptors are expressed in many tissues and organ to regulate their physiological functions. Studies have shown that Apelin/apelin-receptor also expressed in ovary such as follicles, granulosa cells. Furthermore, Apelin/apelin-receptor play roles in vascular establishment and hormone metabolism in ovary. These indicate that the Apelin/apelin-receptor play an important role in the development of follicle. Apelin/apelin-receptor are increased in ovary of PCOS, which are associated with abnormal ovarian hormones and function. These are important causes of menstrual cycle disorders and anovulation. Moreover, apelin now appears clearly as a new player in energy metabolism. Apelin can regulate glucose and lipid metabolism but also modulate insulin secretion. And plasma apelin concentrations are elevated in obesity and type 2 diabetes patients. Interestedly, obesity and type 2 diabetes are also companied with polycystic ovary syndrome patients. We speculate apelin/apelin-receptor may play a vital role in pathogenesis of polycystic ovary syndrome, but the underlying mechanisms remain under exploration. Here, we review apelin/apelin-receptor, as a new therapeutic target, have effects on ovarian function and energy metabolism in polycystic ovary syndrome.

Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy.

Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti-angiogenic treatment has limited efficacy due to therapy-induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy-induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid-derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti-angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor-induced metastases, and high Apelin levels correlate with poor prognosis of anti-angiogenic therapy patients. These data identify a druggable anti-angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.

Prognostic Role of Apelin Receptor Expression in Hepatocellular Carcinoma Treated With Curative Surgical Resection.

BACKGROUND/AIM: apelin and apelin receptor (APJR) are involved in the regulation of angiogenesis, and their high expression is related to poor outcomes in several cancer types. Recently, several positive results on APJR antagonists in cancer treatment have been reported at the preclinical level. The aim of this study was to evaluate the prognostic effect of APJR expression on hepatocellular carcinoma (HCC) survival. MATERIALS AND METHODS: We evaluated APJR expression in 288 curatively resected HCCs using immunohistochemistry and investigated the correlation with clinicopathological features. RESULTS: High APJR expression was significantly associated with the presence of microvascular invasion (p<0.001), intrahepatic metastasis (p=0.004), and early recurrence (p=0.029). The high-expression group showed shorter recurrence-free survival (p<0.001) and overall survival (p=0.001) than the low-expression group. In multivariate analysis, high APJR expression was an independent predictor of shorter recurrence-free survival (Hazard Ratio 1.49; 95% confidence interval 1.08-2.05, p=0.016). CONCLUSION: We described-high APJR expression and its prognostic effect in HCC. Emerging target agents may be applicable in patients with HCC and high APJR expression.