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Apelin Signaling Pathway


Figure 1. Apelin signaling pathway

An overview of apelin

There are many substances that relax blood vessels in the body, such as NO, prostacyclin, vasoactive intestinal peptide, etc. Recently, another vasodilator substance, Apelin, has been discovered. In 1993, Carroll et al. discovered a protein similar in structure to angiotensin II type 1 receptor, named angiotensin type 1 receptor-associated protein, also known as APJ, which belongs to the G-protein coupled family. In 1998, Tatemoto et al. extracted the APJ endogenous ligand named Apelin from bovine gastric secretion,  which is a new adipocytokine and forms an Apelin/APJ system with APJ. Apelin is homologous to angiotensin II (AngII) and is a new member of the renin-angiotensin system (RAS). Apelin has many biological effects such as lowering blood pressure, regulating heart and blood vessel contraction, insulin secretion, pituitary hormone release, and humoral balance. The Apelin/APJ system together with AngII-AT1 antagonism maintains blood pressure homeostasis, and the imbalance between the two may be an important factor in the development of hypertension. Recently, studies have found that Apelin may be associated with heart diseases such as heart failure, coronary heart disease, atrial fibrillation, and as a new adipokine, Apelin is expressed in obesity with insulin resistance, regulation of fatty insulin axis and obesity-related diseases (such as hypertension, type 2 diabetes, etc.). In addition, Apelin can also inhibit the release of vasopressin, which has a diuretic effect, and has a certain relationship with kidney disease.

Apelin family

Carroll et al. found that Apelin mRNA was expressed in the mammary gland, lung, cardiovascular, brain, kidney, testis, ovary and skeletal muscle of rats, and expressed in the breast and lung, vascular endothelium, adipose tissue and gastric parietal cells. In humans, Apelin is mainly expressed in vascular endothelial cells of heart, kidney and lung, and is less expressed in cardiomyocytes, lung, kidney, adrenal secretory cells, vascular smooth muscle cells, adipose tissue, and nerve cells. The human apelin gene is located on chromosome Xq25-26 and consists of three exons and two introns. The mRNA length is 2673 bp. The Apelin precursor peptide contains 77 amino acids, of which 1-22 are signal peptides. After purification, Apelin exists in various subtypes, including Apelin-36, Apelin-31, Apelin-28, Apelin-19, Apelin-13, Apelin-12, etc., of which Apelin-36 and Apelin-13 are more common. Apelin36 is the main form of endogenous Apelin, while Apelin-13 is a form of short peptide. Different peptides may have different biological functions. Apelin is widely distributed in various tissues of the body and can play a biological role as an autocrine or paracrine substance, suggesting that it may participate in the regulation of various physiological and pathological processes in the body.

Apelin signaling pathway

  1. Apelin signaling pathway cascade
    Among the mechanisms of hypertension, the most important is RAS. RAS can regulate water-sodium balance and vasoconstriction tension and plays an important role in the development of hypertension. The most important factor in RAS is undoubtedly AngII. Apelin is a new member of RAS that has just been discovered, shares homology with AngII, and is involved in the regulation of blood pressure. NO produced by endothelial cells is one of the main factors of vasodilation and is closely related to the treatment of hypertension. Apelin's antihypertensive mechanism mainly relies on the NOS/NO pathway to antagonize the boosting effect of AngII and achieve the effect of blood pressure reduction. Ishida et al. also confirmed that Apelin's vasodilator and antihypertensive effects pass through the NO pathway. In hypertensive rats, elevated levels of the Apelin/APJ system are shown to reverse-regulate the AngII-AT1R signaling pathway, resulting in decreased AT1R expression and reduced NO inactivation. AngII is capable of producing reactive oxygen species, which impairs phosphatidylinositol 3-kinase (PI3K)-dependent phosphorylation of Akt /eNOS, reduces NO production, and leads to effective vasoconstriction. The balance of NO-AngII is the key to maintaining vascular tone and blood pressure stability. Apelin/APJ signal abnormality may disrupt the balance between the two, which will lead to the development of hypertension. Apelin (especially Apelin-36) and receptor APJ mRNA are expressed at high levels in the heart and have a positive inotropic effect on the heart. In hypertensive patients, RAS is activated in the circulation, causing vasoconstriction, elevated blood pressure, and hypertrophy of cardiomyocytes, while excessive activation of RAS in local myocardial tissue leads to myocardial remodeling by promoting collagen deposition and fibrosis. The concentration of Apelin in the plasma and left ventricle of the hypertensive rats was significantly higher than that of the normal group. Chen et al found that Apelin levels were elevated in plasma in patients with early heart failure (NYHA1, 2), with NYHA2 being the most elevated. Apelin has the function of dilating blood vessels and lowering blood pressure, which can reduce the load of heart, improve left ventricular hypertrophy caused by anti-hyperrenal and high AngII, and improve cardiac function. Japp et al confirmed that Apelin not only has a cardioprotective effect on patients with chronic heart disease, but also has a protective effect on acutely injured myocardium. Therefore, it is believed that Apelin/APJ system may play a role in the treatment of heart failure in the future. It has been found that Apelin can be secreted by fat cells and is a new adipokine. Studies have also shown that in vitro culture of undifferentiated preadipocytes secretes Apelin. The level of Apelin mRNA in the cultured fat cells is close to that of tissues known to have high expression of Apelin such as heart and kidney. Wei et al found that Apelin and APJ mRNA expression were observed in isolated murine adipocytes, and Apelin mRNA expression increased gradually from 3T3-L1 to adipocytes. Heinomen et al found that the level of Apelin in basal plasma was significantly higher in obese patients than in the control group, and it was positively correlated with body mass index, indicating that Apelin was significantly associated with obesity. It is well known that obese patients are often accompanied by insulin resistance, so it is speculated that the expression of Apelin may be related to the occurrence and development of insulin resistance. Insulin resistance is one of the causes of diabetes, and it can be considered that Apelin expression has a certain relationship with diabetes. Studies have confirmed that Apelin is clearly expressed in renal vascular endothelial cells and is less expressed in epithelial cells. Its receptor APJ is expressed in glomerular endothelial cells, podocytes, collecting ducts, etc., and is expressed most in glomeruli. Apelin/APJ system can not only regulate renal blood flow or glomerular filtration rate, but also regulate the function of the renal tubules. Reaux et al used in situ hybridization and immunohistochemistry to confirm the presence of Apelin-containing neurons in the supraoptic and paraventricular nucleus of rats, and Apelin receptor mRNA in neurons that synthesize vasopressin (VP). VP’s release was reduced in this area after injection of Apelin. According to this, Apelin can inhibit VP synthesis, weaken antidiuretic effect and increase urine output.
  2. Pathway regulation
    Heinomen et al found in the study that the plasma concentrations of Apelin and leptin were significantly higher in obese patients than in the non-obese control group, and that the Apelin and leptin plasma concentrations and body mass index were significantly correlated.  Since the expression of different adipokines, such as leptin and plasminogen activator inhibitor 1, can be regulated by TNF-α, studies have been conducted as to whether Apelin can be regulated by TNF-α. The study group underwent primary culture of subcutaneous adipose tissue of moderate obesity (body mass index 20.5 to 36.5) and morbid obesity (body mass index 39.2 to 59.3). The levels of TNF-α and Apelin mRNA were significantly increased after 3 h of culture, and Apelin mRNA increased after 12h. When 3-isobutyl-1-methylxanthine (a TNF-α inhibitor) was added to the medium, the increase in Apelin mRNA was inhibited. It is suggested that endogenous TNF-α exerts a paracrine regulation effect on Apelin mRNA production by adipocytes. Daviaud et al also injected intraperitoneal TNF-α into the C57BL6J mouse model and observed a significant increase in plasma Apelin concentration. The adipose tissue was isolated after 8 hours of injection, and the expression of Apelin was detected to increase. This suggests that TNF-α up-regulates the expression of Apelin in adipose tissue and further increases plasma Apelin concentration. They delved into the related signal transduction pathways by adding various signal transduction inhibitors and found that this pathway is through mitogen-activated protein kinase, c-Jun amino-terminal kinase and non-protein kinase C pathway.
  3. Relationship with disease
    Heart failure
    The high-level expression of Apelin and its receptor APJ in the cardiovascular system suggests that it plays an important role in the occurrence and development of chronic heart failure (CHF). Chen et al. showed that Apelin levels increased in the early stage of heart failure and decreased in the late stage. However, after the left ventricular assist device was implanted to improve cardiac function, Apelin levels were significantly higher than that before implantation. Although the above results are different, they all suggest that Apelin may be involved in the pathophysiological process of CHF.
    Coronary heart disease
    Li et al. found that plasma Apelin levels were decreased in patients with stable angina, and plasma Apelin levels were negatively correlated with coronary stenosis. Kadoqlou et al also found that plasma Apelin levels were significantly lower in patients with coronary heart disease, and Apelin levels were significantly lower in patients with acute coronary syndrome than in patients with occult coronary heart disease (P < 0.05); and Apelin levels were associated with coronary heart disease and the severity and acute degree were negatively correlated. It is speculated that Apelin may be involved in the formation of coronary atherosclerosis.
    Diabetes
    Recent studies have found that Apelin is an adipokine secreted by adipose tissue, which is up-regulated in obese conditions and may affect glucose metabolism. Zhang et al. measured plasma Apelin levels in 75 newly diagnosed diabetic patients and found that plasma Apelin levels were significantly lower in the diabetic group, and Apelin levels were negatively correlated with C-reactive protein, insulin resistance index, fasting blood glucose, and glycosylated hemoglobin. It is speculated that Apelin is necessary to maintain insulin sensitivity in the body.
    Lung disease
    Goetze et al detected 53 patients with chronic pulmonary parenchymal disease with normal heart function. The results showed that although the plasma proBNP level did not change in patients with chronic pulmonary parenchyma, the plasma Apelin-36 level was decreased by 3.3 times (P < 0.001). It is suggested that the combined determination of Apelin-36 and pro-BNP may be used as a new detection method to identify pulmonary-derived and cardiogenic dyspnea, but many experiments are needed to further support it.

References

  1. Folino A, Montarolo P G, Samaja M, et al. Effects of apelin on the cardiovascular system. Heart Failure Reviews. 2015, 20(4):505-518.
  2. Cheng W, Wen J, Yun Z, et al. Apelin induces vascular smooth muscle cells migration via, a PI3K/Akt/FoxO3a/MMP-2 pathway. International Journal of Biochemistry & Cell Biology. 2015, 69:173-182.
  3. Li C, Yong T, Jiang Y R. Apelin activates the expression of inflammatory cytokines in microglial BV2 cells via PI-3K/Akt and MEK/Erk pathways. Science China Life Sciences. 2015, 58(6):531-540.
  4. Nagib A M, Eldiasty A, El Husseny M A, et al. Apelin and New-Onset Diabetes After Transplant in Living Kidney Allograft Recipients. Experimental & Clinical Transplantation Official Journal of the Middle East Society for Organ Transplantation. 2015, 13(4):319.
  5. Than A, He H L, Si H C, et al. Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes. Journal of Biological Chemistry. 2015, 290(23):14679-14691.

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