Abstract
BackgroundThe peptide apelin is expressed in human healthy livers and is implicated in the development of hepatic fibrosis and cirrhosis. Mutations in the bone morphogenetic protein receptor type II (BMPR-II) result in reduced plasma levels of apelin in patients with heritable pulmonary arterial hypertension. Ligands for BMPR-II include bone morphogenetic protein 9 (BMP9), highly expressed in liver, and BMP10, expressed in heart and to a lesser extent liver. However, it is not known whether reductions in BMP9 and/or BMP10, with associated reduction in BMPR-II signalling, correlate with altered levels of apelin in patients with liver fibrosis and cirrhosis. MethodsPlasma from patients with liver fibrosis (n = 14), cirrhosis (n = 56), and healthy controls (n = 25) was solid-phase extracted using a method optimised for recovery of apelin, which was measured by ELISA. ResultsPlasma apelin was significantly reduced in liver fibrosis (8.3 ± 1.2 pg/ml) and cirrhosis (6.5 ± 0.6 pg/ml) patients compared with controls (15.4 ± 2.0 pg/ml). There was no obvious relationship between apelin and BMP 9 or BMP10 previously measured in these patients. Within the cirrhotic group, there was no significant correlation between apelin levels and disease severity scores, age, sex, or treatment with β-blockers. ConclusionsApelin was significantly reduced in plasma of patients with both early (fibrosis) and late-stage (cirrhosis) liver disease. Fibrosis is more easily reversible and may represent a potential target for new therapeutic interventions. However, it remains unclear whether apelin signalling is detrimental in liver disease or is beneficial and therefore, whether an apelin antagonist or agonist have clinical use.
Highlights
The peptide apelin-36 was identified in 1998 from bovine stomach as the endogenous ligand for an orphan Class A, G protein-coupled receptor encoded by the angiotensin-like-receptor 1 (AGTRL1, known as APJ) gene
Apelin has emerged as having an important role in normal cardiovascular physiology, increasing cardiac contractility and acting in an autocrine/paracrine manner to cause vasodilatation by binding to apelin receptors expressed on endothelial cells to release vasodilators [3,4]
We have previously discovered that levels of bone morphogenetic protein 9 (BMP9) and 10 are significantly reduced in the plasma of patients with cirrhosis compared with healthy controls [23]
Summary
The peptide apelin-36 was identified in 1998 from bovine stomach as the endogenous ligand for an orphan Class A, G protein-coupled receptor encoded by the angiotensin-like-receptor 1 (AGTRL1, known as APJ) gene. Apelin protein expression, measured by western blotting, was increased in the cirrhotic compared to healthy liver, localising to peri portal capillary endothelial cells and proliferated arterial capillaries in the fibrotic septa [6]. The peptide apelin is expressed in human healthy livers and is implicated in the development of hepatic fibrosis and cirrhosis. Mutations in the bone morphogenetic protein receptor type II (BMPR-II) result in reduced plasma levels of apelin in patients with heritable pulmonary arterial hypertension. Ligands for BMPR-II include bone morphogenetic protein 9 (BMP9), highly expressed in liver, and BMP10, expressed in heart and to a lesser extent liver It is not known whether reductions in BMP9 and/or BMP10, with associated reduction in BMPR-II signalling, correlate with altered levels of apelin in patients with liver fibrosis and cirrhosis. It remains unclear whether apelin signalling is detrimental in liver disease or is beneficial and whether an apelin antagonist or agonist have clinical use
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