title: Azelnidipine is a calcium blocker that attenuates liver fibrosis and may increase antioxidant defence.
abstract: OBJECTIVE
  Oxidative stress plays a critical role in liver fibrogenesis. Reactive oxygen species (ROS) stimulate hepatic stellate cells (HSCs), and ROS-mediated increases in calcium influx further increase ROS production. Azelnidipine is a calcium blocker that has been shown to have antioxidant effects in endothelial cells and cardiomyocytes. Therefore, we evaluated the anti-fibrotic and antioxidative effects of azelnidipine on liver fibrosis.
  
  
  METHODS
  We used TGF-β1-activated LX-2 cells (a human HSC line) and mouse models of fibrosis induced by treatment with either carbon tetrachloride (CCl(4) ) or thioacetamide (TAA).
  
  
  RESULTS
  Azelnidipine inhibited TGF-β1 and angiotensin II (Ang II)-activated α1(I) collagen mRNA expression in HSCs. Furthermore, TGF-β1- and Ang II-induced oxidative stress and TGF-β1-induced p38 and JNK phosphorylation were reduced in HSCs treated with azelnidipine. Azelnidipine significantly decreased inflammatory cell infiltration, pro-fibrotic gene expressions, HSC activation, lipid peroxidation, oxidative DNA damage and fibrosis in the livers of CCl(4) - or TAA-treated mice. Finally, azelnidipine prevented a decrease in the expression of some antioxidant enzymes and accelerated regression of liver fibrosis in CCl(4) -treated mice.
  
  
  CONCLUSIONS
  Azelnidipine inhibited TGF-β1- and Ang II-induced HSC activation in vitro and attenuated CCl(4) - and TAA-induced liver fibrosis, and it accelerated regression of CCl(4) -induced liver fibrosis in mice. The anti-fibrotic mechanism of azelnidipine against CCl(4) -induced liver fibrosis in mice may have been due an increased level of antioxidant defence. As azelnidipine is widely used in clinical practice without serious adverse effects, it may provide an effective new strategy for anti-fibrotic therapy.
authors.affiliation: Departments of Medicine and Molecular Science Biochemistry, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ohyama
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: K
authors.initials: K
authors.lastname: Kishimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: N
authors.initials: N
authors.lastname: Horiguchi
authors.forename: T
authors.initials: T
authors.lastname: Ichikawa
authors.forename: S
authors.initials: S
authors.lastname: Kakizaki
authors.forename: H
authors.initials: H
authors.lastname: Takagi
authors.forename: T
authors.initials: T
authors.lastname: Izumi
authors.forename: M
authors.initials: M
authors.lastname: Mori
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D002251:Carbon Tetrachloride; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013853:Thioacetamide; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002121:Calcium Channel Blockers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004095:Dihydropyridines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D013853:Thioacetamide; D000804:Angiotensin II; D001383:Azetidinecarboxylic Acid; D002251:Carbon Tetrachloride; C061679:azelnidipine; D002118:Calcium