The hepatic apelin system: a new therapeutic target for liver disease.
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.


CONCLUSIONS
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.
Principe
Alessandro
A
Biochemistry and Molecular Genetics Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, University of Barcelona, Barcelona, Spain.
Melgar-Lesmes
Pedro
P
Fernández-Varo
Guillermo
G
del Arbol
Luis Ruiz
LR
Ros
Josefa
J
Morales-Ruiz
Manuel
M
Bernardi
Mauro
M
Arroyo
Vicente
V
Jiménez
Wladimiro
W
D000328:Adult; D000818:Animals; D000073861:Apelin; D001794:Blood Pressure / Q000187:drug effects; D002251:Carbon Tetrachloride; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects
C115436:APLN protein, human; D000073861:Apelin; C498579:Apln protein, rat; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C495199:apelin-13 peptide; C532492:apelin-13, Ala(13)-; D002251:Carbon Tetrachloride