The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells, reducing procollagen gene expression in rat liver fibrosis induced by choline-deficient L-amino acid-defined diet.
No effective therapy has yet developed for liver fibrosis by directory inhibiting the accumulation of extracellular matrix. The effect of a newly synthesized prolyl4-hydroxylase (PH) inhibitor, HOE 077 (pyridine-2, 4-di-carboxylic-di(2-methoxyethyl)amide), was examined using the model of choline-deficient L-amino acid (CDAA) defined diet-induced liver fibrosis in 16-week-old male Wistar rats. HOE 077 at doses up to 200 ppm prevented fibrosis in a dose-dependent manner, as indicated by reduced hydroxyproline content in liver as well as inhibition of increased serum fibrotic markers (PIIIP, 7S, hyaluronic acid). HOE 077 at 200 ppm reduced expression of type III procollagen alpha 1, messenger RNA (mRNA) in the liver, with a good correlation with serum PIIIP and hydroxyproline content of the liver. Histologically, HOE 077 at 200 ppm also reduced proliferation of myofibroblastlike cells (activated Ito cells). These results indicate that a PH inhibitor can prevent fibrosis by inhibiting not only the hydroxylation of proline but also the activation of Ito cells, which are considered the main collagen-producing cells, resulting in reduced expression of procollagen mRNA.
Sakaida
I
I
First Department of Internal Medicine, School of Medicine, Yamaguchi University, Japan.
Matsumura
Y
Y
Kubota
M
M
Kayano
K
K
Takenaka
K
K
Okita
K
K
D000596:Amino Acids / Q000172:deficiency*; D000818:Animals; D002796:Choline Deficiency / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006909:Hydroxyproline / Q000032:analysis; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D011347:Procollagen / Q000235:genetics*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
D000596:Amino Acids; D011347:Procollagen; D011725:Pyridines; D012333:RNA, Messenger; C074630:lufironil; D011393:Procollagen-Proline Dioxygenase; D006909:Hydroxyproline