br The role of apelin

The role of apelin in hypertension diseases The role of apelin and its receptor APJ in cardiovascular diseases has been described in numerous studies (Table 2) [36,37]. It has been revealed that exogenous apelin may lower blood pressure. Tatemoto et al. [6] have discovered that different forms of apelin (36, 13 and 12) at a dose of 10 nmol/kg injected into the right femoral vein of anaesthetized rats reduce blood pressure; however, this effect is blocked by nitric oxide (NO) synthase inhibitor. It should be emphasized that the reduction of blood pressure by apelin-12 is stronger than by its other molecular forms. In contrast, Zhang et al. [38] have noticed that direct microinjection of exogenous apelin-13 (200 pmol in 50 nl) into the rostral ventrolateral medulla of spontaneously hypertensive rats causes a blood pressure increase. Hence, it could be suggested that apelin action on blood pressure depends on the route of administration [38]. An ability to vasodilate is another feature of apelin action. It can block the vasoconstrictive effect of Ang-II and can promote the vasodilative effect of NO [39,40]. Moreover, the apelin/APJ system has a stimulatory effect on endothelial cell proliferation in the presence of vascular endothelial growth factor and may be involved in the regulation of blood vessel diameter during angiogenesis [41]. The apelin/APJ system also inhibits sodium retention and increases secretion of an antidiuretic hormone AVP and, as a result, lowers blood pressure [40]. There is also evidence that the apelin/APJ system may be involved in the prolyl hydroxylase of adhesion molecules and chemokine variation in endothelial cells, which may promote endothelial injury of vessels and aggravated hypertension [42]. In a clinical study on a Caucasian population, it has been found that a low apelin level in circulation can be a cause of hypertension [43]. Therefore, it is thought that the apelin/APJ system may be a promising therapeutic target for hypertension.
The role of apelin in metabolic disorders Recent evidence suggests that the apelin/APJ system may be considered as an emerging therapeutic target for treatment of insulin resistance and type 2 diabetes (Table 3). For example, in a clinical study conducted on healthy overweight men during hyperinsulinaemic-euglycaemic clamps, the intravenous administration of 30nmol/kg (Pyr1)-apelin-13 increased the glucose infusion rate (GIR) and improved insulin sensitivity [44]. Additionally, in an in vitro experiment on isolated adipocytes obtained from obese patients, apelin stimulated 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and glucose uptake but had no effect on lipolysis [45]. However, in patients with gestational diabetes mellitus, plasma apelin levels and apelin/APJ mRNA expression did not influence the disease course. In addition, there were no differences observed in insulin levels between the patients with gestational diabetes mellitus and healthy pregnant women [46]. Energy metabolism is another field of the apelin/APJ system action. Intravenous administration of apelin at a physiological dose decreases glycemia and enhances glucose utilization in skeletal muscle and adipose tissue in normal and obese insulin-resistant mice [47]. Administration of (pGlu)-apelin-13 amide to a diet-induced diabetes mouse model reduces glycated haemoglobin (HbA1c) and glucose levels in blood. In these mice, LDL cholesterol and circulating triglycerides are also reduced but circulating total glucagon-like peptide 1 (GLP-1) and insulin concentrations are increased [48]. In addition, apelin may enhance glucose utilization and improve insulin sensitivity. Hwangbo et al. [49] have found that in mice, apelin serves as an inhibitor of fatty acid transport across the endothelial layer, and this process is dependent on apelin-induced inactivation of the transcription factor Forkhead box protein O1 (FOXO1) in the endothelium of skeletal muscle. This inactivation causes suppression of the endothelial fatty acid-binding protein 4 (FABP4) expression. So, the apelin/APJ system is considered as a therapeutic target for type 2 diabetes and related metabolic disorders and may improve glycaemic control while reversing endothelial dysfunction [49].