Overexpression of apelin receptor (APJ/AGTRL1) on hepatic stellate cells and sinusoidal angiogenesis in human cirrhotic liver.
BACKGROUND
The apelin receptor (APJ) is related to angiotensin-like-receptor 1 (AGTRL1). This study was designed to elucidate the in vivo localization and changes of APJ in cirrhotic liver, and the in vitro changes of APJ expression in cultured hepatic stellate cells (HSCs) and capillarized sinusoidal endothelial cells (SECs) activated by growth factors.


METHODS
In vivo studies used control liver samples, cirrhotic liver samples from patients with Child's A cirrhosis undergoing surgical resection (Child-A-LC), and cirrhotic liver samples from autopsied cases of decompensated Child's C cirrhosis (Child-C-LC). Immunohistochemical (IHC), Western blot, laser-capture microdissection (LCM) coupled with reverse transcription -polymerase chain reaction (RT-PCR), and immunoelectron microscopic (IEM) studies for APJ expression were conducted. In vitro examinations used commercial human HSCs and SECs. APJ expression was examined in cultured HSCs activated by growth factors and in capillarized SECs activated by angiogenic factors.


RESULTS
The IHC study of liver samples revealed only slight APJ expression in hepatic sinusoids in control liver tissue. In cirrhotic liver (Child-A-LC and Child-C-LC), APJ expression was evident mainly along the sinusoids and on portal fibroblasts in fibrotic septa. Western blot analysis of whole-liver homogenate and LCM-PCR of sinusoids revealed overexpression of APJ in Child-C-LC samples. The results of IEM studies showed that APJ expression was increased significantly on HSCs, but it was sparse on SECs in Child-C-LC tissue. In vitro examination revealed that APJ was overexpressed in cultured HSCs activated by platelet-derived growth factor-β.


CONCLUSIONS
Enhanced expression of APJ on HSCs in cirrhosis indicates markedly increased vascular remodeling.
Yokomori
Hiroaki
H
Department of Internal Medicine, Kitasato Institute Medical Center Hospital, Kitasato University, 6-100 Arai, Kitamoto, Saitama 364-8501, Japan. yokomori@insti.kitasato-u.ac.jp
Oda
Masaya
M
Yoshimura
Kazunori
K
Machida
Sanae
S
Kaneko
Fumihiko
F
Hibi
Toshifumi
T
D000368:Aged; D000369:Aged, 80 and over; D000075244:Apelin Receptors; D001158:Arteries / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006503:Hepatic Veins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009389:Neovascularization, Pathologic; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
C104575:APLNR protein, human; D000075244:Apelin Receptors; D010982:Platelet-Derived Growth Factor; D043562:Receptors, G-Protein-Coupled; D042461:Vascular Endothelial Growth Factor A