TY - JOUR

T1 - Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor-dependent inhibition of hepatic stellate cell contraction

AU - Endutkin, A.

AU - Popov, A.

AU - Yudkina, A.

AU - Makasheva, K.

AU - Afonnikov, D.

AU - Simmerling, C.

AU - Zharkov, D.

N1 - © 2016 Federation of European Biochemical Societies.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl 4-caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl 4-administrated rat HSC but an increase in that in DHA-treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl 4-induced liver injury. DHA also reduced CCl 4-caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT-747 but weakened by Z-guggulsterone. Noteworthily, DHA, analogous to INT-747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction via a FXR activation-dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis.

AB - Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl 4-caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl 4-administrated rat HSC but an increase in that in DHA-treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl 4-induced liver injury. DHA also reduced CCl 4-caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT-747 but weakened by Z-guggulsterone. Noteworthily, DHA, analogous to INT-747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction via a FXR activation-dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis.

KW - contraction

KW - dihydroartemisinin

KW - farnesoid X receptor

KW - hepatic stellate cell

KW - portal hypertension

KW - Portal Vein/drug effects

KW - Carbon Tetrachloride

KW - Humans

KW - Male

KW - Cell Death/drug effects

KW - Gene Expression

KW - Liver/blood supply

KW - Rats

KW - Hepatocytes/drug effects

KW - Mice, Transgenic

KW - Chenodeoxycholic Acid/analogs & derivatives

KW - Protective Agents/pharmacology

KW - Rats, Sprague-Dawley

KW - Mice, Inbred ICR

KW - Receptors, Cytoplasmic and Nuclear/agonists

KW - Liver Cirrhosis/chemically induced

KW - Hypertension, Portal/chemically induced

KW - Animals

KW - Hepatic Stellate Cells/drug effects

KW - Mice

KW - Pregnenediones/pharmacology

KW - Artemisinins/pharmacology

UR - http://www.scopus.com/inward/record.url?scp=85006128063&partnerID=8YFLogxK

U2 - 10.1111/febs.13956

DO - 10.1111/febs.13956

M3 - Article

C2 - 27896916

VL - 284

SP - 114

EP - 133

JO - FEBS Journal

JF - FEBS Journal

SN - 1742-464X

IS - 1

T2 - 42nd Congress of the Federation-of-European-Biochemical-Societies (FEBS) on From Molecules to Cells and Back

Y2 - 10 September 2017 through 14 September 2017

ER -