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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Br+J+Pharmacol
2017 ; 174
(5
): 409-423
Nephropedia Template TP
Zhang F
; Hao M
; Jin H
; Yao Z
; Lian N
; Wu L
; Shao J
; Chen A
; Zheng S
Br J Pharmacol
2017[Mar]; 174
(5
): 409-423
PMID28052321
show ga
BACKGROUND AND PURPOSE: Hepatic stellate cells (HSCs) are liver-specific
pericytes regulating angiogenesis during liver fibrosis. We aimed to elucidate
the mechanisms by which hedgehog signalling regulated HSC angiogenic properties
and to validate the therapeutic implications. EXPERIMENTAL APPROACH: Rats and
mice were treated with carbon tetrachloride for in vivo evaluation of hepatic
angiogenesis and fibrotic injury. Diversified molecular approaches including
real-time PCR, Western blot, luciferase reporter assay, chromatin
immunoprecipitation, electrophoretic mobility shift assay and
co-immunoprecipitation were used to investigate the underlying mechanisms in
vitro. KEY RESULTS: Angiogenesis was concomitant with up-regulation of Smoothened
(SMO) and hypoxia inducible factor-1? (HIF-1?) in rat fibrotic liver. The SMO
inhibitor cyclopamine and Gli1 inhibitor GANT-58 reduced expression of VEGF and
angiopoietin 1 in HSCs and suppressed HSC tubulogenesis capacity. HIF-1?
inhibitor PX-478 suppressed HSC angiogenic behaviour, and inhibition of hedgehog
decreased HIF-1? expression. Furthermore, heat shock protein 90 (HSP90) was
characterized as a direct target gene of canonical hedgehog signalling in HSCs.
HSP90 inhibitor 17-AAG reduced HSP90 binding to HIF-1?, down-regulated HIF-1?
protein abundance and decreased HIF-1? binding to DNA. 17-AAG also abolished
1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) (a SMO agonist)-enhanced HSC
angiogenic properties. Finally, the natural compound ligustrazine was found to
inhibit canonical hedgehog signalling leading to suppressed angiogenic properties
of HSCs in vitro and ameliorated liver fibrosis and sinusoidal angiogenesis in
mice. CONCLUSION AND IMPLICATIONS: We have provided evidence that the canonical
hedgehog pathway controlled HSC-mediated liver angiogenesis. Selective inhibition
of HSC hedgehog signalling could be a promising therapeutic approach for hepatic
fibrosis.
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