The hepatic apelin system

Abstract

Apelin is a peptide that plays an important role in heart physiology and pathophysiology, inflammation, and angiogenesis. We evaluated whether the endogenous apelin system is involved in the pathogenesis of the hepatic remodeling and cardiovascular and renal complications occurring in advanced liver disease. The circulating levels of apelin, the messenger RNA (mRNA) and protein expression of apelin and apelin receptor, the immunohistological detection of apelin and apelin receptor, and the effects induced by the chronic administration of an apelin receptor antagonist on fibrosis and vessel density were evaluated in rats with cirrhosis and ascites and in control rats. The serum levels of apelin in patients with cirrhosis were also measured. Apelin levels were higher in rats with cirrhosis than in controls. Apelin mRNA showed a four-fold rise only in hepatic tissue, but not in the lung, heart, or kidney of rats with cirrhosis. These animals also showed hepatic apelin receptor mRNA levels 300 times higher than controls. Apelin was highly expressed by stellate cells, whereas apelin receptor was overexpressed in the hepatic parenchyma of animals with cirrhosis. Rats with cirrhosis treated with the apelin receptor antagonist showed diminished hepatic fibrosis and vessel density, improved cardiovascular performance, and renal function and lost ascites. Human patients also showed a marked increase in apelin levels. Conclusion: The selective hepatic activation of the apelin system, together with the drop in fibrosis and neoangiogenesis and the improvement in cardiovascular and excretory function resulting from apelin receptor blockade, points to the hepatic apelin system as a novel therapeutic target in liver disease. (HEPATOLOGY 2008;48:1193-1201

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…In brain tumours, the expression of apelin and APJ is up-regulated in microvascular proliferations (Kalin et al 2007), while tumour cell lines overexpressing apelin show increased growth (Sorli et al 2007). The pathophysiological effects of apelin in angiogenesis have also been reported for the liver, where the apelinergic system is a factor in portosystemic collaterisation and splanchnic neovascularisation in portal hypotensive rats (Tiani et al 2009) as well as in neovascularisation during liver cirrhosis (Principe et al 2008). However, apelin may have therapeutic effects in ischaemia recovery due to vessel regeneration and endothelial proliferation (Eyries et al 2008) and blood vessel diameter regulation (Kidoya et al 2010).…”

Cellular and molecular mechanisms in liver fibrogenesis

“…This adipokine represent the the endogenous ligand of the orphan G protein-coupled receptor APJ, and is known to display a pro-angiogenic role [74]. The interest in apelin, which is expressed and secreted by adipose tissue both in mice and humans [75], has been generated by a study reporting that its levels were markedly increased in cirrhotic liver [76]. Apelin was found to be highly expressed by HSCs and in the same study the use of an antagonist of the apelin receptor was reported to inhibit not only angiogenesis but also hepatic fibrosis.…”

International Union of Basic and Clinical Pharmacology. LXXIV. Apelin Receptor Nomenclature, Distribution, Pharmacology, and Function

“…The apelin system is proposed to have a role in pathophysiological angiogenesis, contributing to portosystemic collateralization and splanchnic neovascularization in portal hypertensive rats (Tiani et al, 2009), neoangiogenesis in liver cirrhosis (Principe et al, 2008), and tumor neoangiogenesis (Kä lin et al, 2007;Sorli et al, 2007). However, angiogenic effects (Eyries et al, 2008) and induction of larger nonleaky vessels by apelin (Kidoya et al, 2010) appear to be beneficial in recovery from ischemia.…”