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Am J Transl Res 2013;5(4):465-469
Brief Communication
Peptidyl arginine deiminase inhibitor effect on hepatic fibrogenesis in
a CCl4 pre-clinical model of liver fibrosis
Efstathios Vassiliadis, Sanne Skovgaard Veidal, Maria Nicoline Baandrup Kristiansen, Christina Hansen, Mia
Jorgensen, Diana J Leeming, Morten Karsdal
Assay Development, Nordic Bioscience, Copenhagen, Denmark; Department of Endocrinology, University of
Southern Denmark, Odense, Denmark
Received April 2, 2013; Accepted April 27, 2013; Epub May 24, 2013; Published June 1, 2013
Abstract: Having previously shown that levels of the citrullinated vimentin peptide VICM are raised in liver fibrosis
in rats, we aimed to investigate whether inhibition of citrullination as measured by VICM levels could affect
fibrogenesis. Methods: Fibrogenesis was evaluated by quantitative histology and circulating levels of collagen
type III in a carbon tetrachloride (CCl4) rat model of liver fibrosis for 6 weeks (n=40+10 untreated controls). The
first treatment group (n=20) was treated exclusively with CCl4 for the duration of the study.The second treatment
group (n=20) was additionally treated, for the same period, with N-a-benzoyl-N5-(2
Chloro-1-iminoethyl)-L-Ornithine amide, a known PAD inhibitor. Results: All 40 CCl4 treated animals showed a
statistically significant increase in total collagen (p<0.0001) and C3M levels (p<0.001) compared with controls
assessed by quantitative histology. Animals additionally treated with the PAD inhibitor showed a statistically
significant increase when compared with controls for both total collagen (p<0.001) and C3M levels (p<0.0001) but
no statistically difference when compared with animals treated only with CCl4. The mean systemic level of VICM
in control animals was 115 ng/ml at 6 weeks. In CCl4-treated animals, mean systemic VICM levels increased
324% at week 6 (p<0.001). The mean level of the marker in CCl4-treated rats was not statistically significant from
that in controls (P>0.05). In PAD-treated animals VICM levels were 51% (P<0.05) lower than in non-PAD
CCl4-treated animals. Conclusion: The PAD inhibitor did not reduce fibrogenesis in this preclinical model.
However circulating VICM marker levels were decreased in the presence of the PAD inhibitor. (AJTR1304002).
Keywords: Biomarker, citrulline, PAD inhibitor, VICM, vimentin, liver fibrosis, CCl4
Address correspondence to: Efstathios Vassiliadis, Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730
Herlev, Denmark. Tel: +45 44547738; Fax: +45 44525251; E-mail: eva@nordicbioscience.com
Brief Communication
Peptidyl arginine deiminase inhibitor effect on hepatic fibrogenesis in
a CCl4 pre-clinical model of liver fibrosis
Efstathios Vassiliadis, Sanne Skovgaard Veidal, Maria Nicoline Baandrup Kristiansen, Christina Hansen, Mia
Jorgensen, Diana J Leeming, Morten Karsdal
Assay Development, Nordic Bioscience, Copenhagen, Denmark; Department of Endocrinology, University of
Southern Denmark, Odense, Denmark
Received April 2, 2013; Accepted April 27, 2013; Epub May 24, 2013; Published June 1, 2013
Abstract: Having previously shown that levels of the citrullinated vimentin peptide VICM are raised in liver fibrosis
in rats, we aimed to investigate whether inhibition of citrullination as measured by VICM levels could affect
fibrogenesis. Methods: Fibrogenesis was evaluated by quantitative histology and circulating levels of collagen
type III in a carbon tetrachloride (CCl4) rat model of liver fibrosis for 6 weeks (n=40+10 untreated controls). The
first treatment group (n=20) was treated exclusively with CCl4 for the duration of the study.The second treatment
group (n=20) was additionally treated, for the same period, with N-a-benzoyl-N5-(2
Chloro-1-iminoethyl)-L-Ornithine amide, a known PAD inhibitor. Results: All 40 CCl4 treated animals showed a
statistically significant increase in total collagen (p<0.0001) and C3M levels (p<0.001) compared with controls
assessed by quantitative histology. Animals additionally treated with the PAD inhibitor showed a statistically
significant increase when compared with controls for both total collagen (p<0.001) and C3M levels (p<0.0001) but
no statistically difference when compared with animals treated only with CCl4. The mean systemic level of VICM
in control animals was 115 ng/ml at 6 weeks. In CCl4-treated animals, mean systemic VICM levels increased
324% at week 6 (p<0.001). The mean level of the marker in CCl4-treated rats was not statistically significant from
that in controls (P>0.05). In PAD-treated animals VICM levels were 51% (P<0.05) lower than in non-PAD
CCl4-treated animals. Conclusion: The PAD inhibitor did not reduce fibrogenesis in this preclinical model.
However circulating VICM marker levels were decreased in the presence of the PAD inhibitor. (AJTR1304002).
Keywords: Biomarker, citrulline, PAD inhibitor, VICM, vimentin, liver fibrosis, CCl4
Address correspondence to: Efstathios Vassiliadis, Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730
Herlev, Denmark. Tel: +45 44547738; Fax: +45 44525251; E-mail: eva@nordicbioscience.com
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