Research output: Contribution to journal › Article › peer-review
Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor-dependent inhibition of hepatic stellate cell contraction. / Endutkin, A.; Popov, A.; Yudkina, A. et al.
In: FEBS Journal, Vol. 284, No. 1, 01.01.2017, p. 114-133.Research output: Contribution to journal › Article › peer-review
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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 -
ID: 18734398