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Recent Research Progress
APLN (also known as Apelin) is an endogenous ligand of angiotensin type 1 receptor-associated protein (APJ), and APJ constitutes the APLN/APJ system. APLN is homologous to angiotensin II (AngII) and is a member of the renin-angiotensin system (RAS). APLN has a variety of biological effects such as lowering blood pressure, regulating cardiac and vascular contractile function, insulin secretion, release of pituitary hormones, and humoral balance. The human APLN gene is located on chromosome Xq25-26.1 and consists of 3 exons and 2 introns. The length of mRNA is 2673 bp. The encoded APLN precursor peptide contains 77 amino acids, of which 1-22 are signal peptides. The active peptide sequence is encoded starting from 42. The C-terminus is a region that specifically binds to the APJ receptor and is required for the specific function of the APLN gene in the arginine rich region. After purification, there are many subtypes of APLN, of which APLN-36 and APLN-13 are more common, APLN-36 is the main form of endogenous APLN, and APLN-13 is a short peptide form with different peptides. In humans, APLN is mainly expressed in vascular endothelial cells of the heart, kidneys, and lungs and is less expressed in cardiomyocytes, lung, kidney, adrenal gland secretory cells, vascular smooth muscle cells, adipose tissue, and nerve cells. It can play a biological role as an autocrine or paracrine substance, suggesting that it may participate in the regulation of a variety of physiological and pathological processes in the body.
Figure 1. Schematic of APLN/APJ-triggered intracellular signal transduction pathways (Yu, et al. 2014).
In the pathogenesis of hypertension, the most important is the RAS. RAS can regulate water sodium balance and vasoconstriction tension, play an important role in the occurrence and development of hypertension. The most important factor in RAS is undoubtedly AngII. APLN shares homologies with AngII and is involved in the regulation of blood pressure. NO produced by endothelial cells is one of the major factors of vasodilation and is closely related to the treatment of hypertension. The antihypertensive mechanism of APLN is mainly through the NOS/NO pathway, which acts to antagonize the vasopressor effect of AngII and achieve the effect of reducing blood pressure.
Positive Inotropic Effect
APLN (especially APLN-36) and receptor APJ mRNA are expressed at high levels in the heart and have a positive inotropic effect on the heart. In hypertensive disease, RAS is activated in the circulation, causing vasoconstriction, elevated blood pressure, hypertrophy of cardiac muscle cells. Excessive activation of RAS in the local myocardial tissue leads to myocardial remodeling by promoting collagen deposition and fibrosis. The concentration of APLN in plasma and left ventricle was significantly higher in two-kidney, one-clip renal hypertension rats than in the normal group. APLN has the function of dilating blood vessels and lowering blood pressure, which can reduce the load of the heart and counteract the left ventricular hypertrophy effect caused by high renin and high Ang II and improve cardiac function.
APLN is secreted by fat cells and is a new fat factor. Undifferentiated preadipocytes cultured in vitro secrete APLN. The level of APLN mRNA in adipocytes cultured in vitro is close to that of well-known APLN-expressing tissues such as heart and kidney. The study found that APLN is significantly associated with obesity. As we all know, obese patients often have insulin resistance, so it is speculated that the expression of APLN may be related to the occurrence and development of insulin resistance.
Studies have confirmed that APLN is significantly 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 highest in glomeruli. It can be seen that APLN/APJ system not only regulates renal blood flow or glomerular filtration rate but also regulates the function of the renal tubules.
APLN and Disease
APLN/APJ system and AngII-AT1 antagonism together maintain blood pressure homeostasis. The imbalance between the two may be an important factor in the development of hypertension. Recently, studies have found that APLN may be associated with heart diseases such as heart failure, coronary heart disease, and atrial fibrillation. At the same time, as a new adipokine, APLN expression is increased in obesity with insulin resistance, and in fat insulin axis regulation and obesity-related diseases (such as hypertension, type 2 diabetes, etc.) also plays an important role. In addition, APLN can also inhibit the release of antidiuretic hormone. So it has a certain relationship with kidney disease.
The study found that APLN can reduce blood pressure by antagonizing the vasopressor action of AngII, and its antihypertensive mechanism is mainly through the NO pathway. With the increase of Ang II concentration and blood pressure, APLN concentration will increase accordingly to antagonize the vasopressor action of Ang II. Then, Ang II concentration will decrease, blood pressure will decrease, and APLN concentration will decrease accordingly. Therefore, it can be considered that there is a correlation between APLN and hypertension. Zhu et al. explored the relationship between single nucleotide polymorphisms (ANPs) in the APLN gene (APLN) and high blood pressure and central retinal artery (CRAE) stenotic hypertension in the coastal areas of China. APLN SNP rs3761581 was found to be associated with hypertension with CRAE and revealed that APLN gene product expression may be involved in vascular injury.
Coronary Heart Disease
APLN is highly expressed in the cardiovascular system and regulates cardiovascular systolic function. It also has a positive inotropic effect on the heart. It has been reported in the literature that the APLN/APJ system is closely related to coronary heart disease. Atherosclerosis is a major factor in the development of coronary heart disease. Studies have reported that APLN levels are lower in patients with stable angina and acute myocardial infarction compared with the normal group. Sans-Roselló found that APLN concentrations are associated with markers of ischemic heart failure severity and plays a key role in the pathophysiology of ischemia/reperfusion injury and subsequent heart failure.
Insulin is one of the main hormones to maintain blood glucose levels in the body. Abnormal insulin secretion and decreased insulin sensitivity often lead to diabetes. The levels of APLN and insulin in the plasma of obese patients are very high, suggesting that insulin may regulate the expression of APLN and affect the concentration of APLN in the blood. Ma et al. found that plasma APLN is a novel biomarker for predicting male type 2 diabetes. APLN is not only regulated by insulin but also likely to affect insulin production. Moreover, APLN not only participates in insulin resistance but also regulates the secretion of insulin, which provides a new idea for the treatment of diabetes. Zheng et al. analyzed the association between single nucleotide polymorphisms (ANPs) of APLN gene and type 2 diabetes mellitus (T2DM) and found that SNP rs2281068 in APLN was significantly associated with diabetes in Chinese population.