Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells

Abstract

Hepatic fibrosis is concomitant with sinusoidal pathological angiogenesis, which has been highlighted as novel therapeutic targets for the treatment of chronic liver disease. Our prior studies have demonstrated that curcumin has potent antifibrotic activity, but the mechanisms remain to be elucidated. The current work demonstrated that curcumin ameliorated fibrotic injury and sinusoidal angiogenesis in rat liver with fibrosis caused by carbon tetrachloride. Curcumin reduced the expression of a number of angiogenic markers in fibrotic liver. Experiments in vitro showed that the viability and vascularization of rat liver sinusoidal endothelial cells and rat aortic ring angiogenesis were not impaired by curcumin. These results indicated that hepatic stellate cells (HSCs) that are characterized as liver-specific pericytes could be potential target cells for curcumin. Further investigations showed that curcumin inhibited VEGF expression in HSCs associated with disrupting platelet-derived growth factor-β receptor (PDGF-βR)/ERK and mTOR pathways. HSC motility and vascularization were also suppressed by curcumin associated with blocking PDGF-βR/focal adhesion kinase/RhoA cascade. Gain- or loss-of-function analyses revealed that activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) was required for curcumin to inhibit angiogenic properties of HSCs. We concluded that curcumin attenuated sinusoidal angiogenesis in liver fibrosis possibly by targeting HSCs via a PPAR-γ activation-dependent mechanism. PPAR-γ could be a target molecule for reducing pathological angiogenesis during liver fibrosis.

Inhibition of Janus kinase-2 signalling pathway ameliorates portal hypertensive syndrome in partial portal hypertensive and liver cirrhosis rats

“…VEGF inhibition by AG490 greatly decreased intrahepatic neovascularization, as shown by diminished CD31 expression. The inhibition of HSC activation may also contribute to the reduction of VEGF expression [26]. Moreover, the inhibition of VEGF expression may also inhibit fibrosis by diminishing HSC activation [6].…”

Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells

“…15 4',6-Diamidino-2-phenylindole (DAPI) was used to stain the nucleus in liver tissues. Hoechst reagent was used to stain the nucleus of HSCs in vitro.…”

“…Protein detection and band visualization and densitometry were performed as we previously described. 15 β-Actin was used as an invariant control for equal loading of total proteins, and Lamin A/C was for nuclear proteins. Representative blots were from three independent experiments.…”

“…14,15,20 In this study, we initially examined the key molecules of Hh signaling in rat fibrotic liver. Results from immunofluorescence staining showed that Patched, Smo, and Hhip were expressed in HSCs indicated by double staining, respectively, with α-smooth muscle actin (α-SMA), the marker of HSC activation.…”

“…13 We demonstrate that curcumin reduces liver fibrosis by attenuating oxidative stress, suppressing inflammation, 14 and inhibiting pathological angiogenesis. 15 Curcumin also inhibits HSC activation associated with interruption of transforming growth factor-β 16 and plateletderived growth factor pathways. 17 However, we hold that the underlying mechanisms are not sufficiently elucidated.…”