Apelin

Apelin (also known as APLN) is a peptide that in humans is encoded by the APLN gene. Apelin is the endogenous is_associated_with::ligand for the G-protein-coupled APJ receptor    that is expressed at the surface of some cell types. It is widely expressed in various organs such as the heart, lung, kidney, liver, is_associated_with::adipose tissue, is_associated_with::gastrointestinal tract, brain, adrenal glands, is_associated_with::endothelium, and human plasma.

Discovery
Apelin is a new peptide that was identified in 1998 by Professor M. Fujino’s team.

Biosynthesis
Apelin gene encodes a pre-proprotein of 77 amino acids, with a is_associated_with::signal peptide in the N-terminal region. After translocation into the is_associated_with::endoplasmic reticulum and cleavage of the signal peptide, the proprotein of 55 amino acids may generate several active fragments: a 36 amino acid peptide corresponding to the sequence 42-77 (apelin 36), a 17 amino acid peptide corresponding to the sequence 61-77 (apelin 17) and a 13 amino acid peptide corresponding to the sequence 65-77 (apelin 13). This latter fragment may also undergo a pyroglutamylation at the level of its N-terminal glutamine residue. However the presence and/or the concentrations of those peptides in human plasma has been questioned. Recently, 46 different apelin peptides ranging from apelin 55 (proapelin) to apelin 12 have been identified in bovine colostrum, including C-ter truncated isoforms.

Physiological functions
The sites of receptor expression are clearly linked to the different functions played by apelin in the organism.

Vascular
Vascular expression of the receptor participates in the control of is_associated_with::blood pressure and its activation promotes the formation of new blood vessels (is_associated_with::angiogenesis). The is_associated_with::hypotensive effect of apelin results from the activation of receptors expressed at the surface of is_associated_with::endothelial cells. This activation induces the release of NO, a potent vasodilator, which induces relaxation of the smooth muscle cells of artery wall. Studies performed on mice knocked out for the apelin receptor gene have suggested the existence of a balance between is_associated_with::angiotensin II signalling, which increases blood pressure and apelin signalling, which lowers blood pressure. The is_associated_with::angiogenic activity is the consequence of apelin action on the proliferation and migration of the endothelial cells. Apelin activates inside the cell transduction cascades (ERKs, Akt, and p70S6kinase phosphorylation), which lead to the proliferation of endothelial cells and the formation of new blood vessels It is interesting that knockout of apelin gene is associated with a delay in the development of the retinal vasculature.

Cardiac
The apelin receptor is expressed early during the embryonic formation of the heart, where it regulates the migration of cell progenitors fated to differentiate in the contractile cells, the is_associated_with::cardiomyocytes. Its expression is also detected in the cardiomyocytes of the adult where apelin behaves as one of the most potent stimulator of cardiac contractility. Aged apelin knockout mice develop progressive impairment of cardiac contractility. Apelin acts as a mediator of the cardiovascular control, including for blood pressure and blood flow. It is one of the most potent stimulators of cardiac is_associated_with::contractility yet identified, and plays a role in cardiac tissue remodeling. Apelin levels are increased in left ventricles of patients with chronic heart failure and also in patients with is_associated_with::chronic liver disease. It is also an adipocyte is_associated_with::endocrine secretion, making adipocytic and circulating levels of apelin higher in obesity. Insulin exerts a positive action on adipocyte apelin production. In addition, apelin regulates fluid homeostasis. It is important in the hypothalamic regulation of food and water intake, and is_associated_with::pituitary is_associated_with::hormone release.

Brain
Apelin receptor is also expressed in the neurons of brain areas involved in water and food intake. Apelin injection increases water intake and apelin decreases in the is_associated_with::hypothalamus the secretion of an antidiuretic is_associated_with::hormone, is_associated_with::vasopressin. This is_associated_with::diuretic effect of apelin in association with its hypotensive effect participates in a global manner to the homeostatic regulation of body fluids. Apelin is also detected in brain areas, which control appetite, but its effects on food intake are very contradictory.

Digestive
Apelin receptor is expressed in several cell types of the is_associated_with::gastro-intestinal tract : is_associated_with::stomach enterochromaffine-like cells; unknown cells of endocrine is_associated_with::pancreas, colon epithelial cells. In stomach, activation of receptors on enterochromaffine-like cells by apelin secreted by is_associated_with::parietal cells can inhibit histamine release by enterochromaffine-like cells, which in turn decreases acid secretion by parietal cells. In pancreas, apelin inhibits the insulin secretion induced by glucose. This inhibition reveals the functional interdependency between apelin signalling and insulin signalling observed at the adipocyte level where insulin stimulate apelin production. Recently, receptor expression was also detected in skeletic muscle cells. Its activation is involved in glucose uptake and participates in the control of glucose blood levels glycemia.

Bone
Receptor expression is also observed at the surface of osteoblasts, the cell progenitors involved in bone formation.