Prevention of liver fibrosis by triple helix-forming oligodeoxyribonucleotides targeted to the promoter region of type I collagen gene.
Hepatic fibrosis leading to cirrhosis remains a global health problem. The most common etiologies are alcoholism and viral infections. Liver fibrosis is associated with major changes in both quantity and composition of extracellular matix and leads to disorganization of the liver architecture and irreversible damage to the liver function. As of now there is no effective therapy to control fibrosis. The end product of fibrosis is abnormal synthesis and accumulation of type I collagen in the extracellular matrix, which is produced by activated stellate or Ito cells in the damaged liver. Therefore, inhibition of transcription of type I collagen should in principle inhibit its production and accumulation in liver. Normally, DNA exists in a duplex form. However, under some circumstances, DNA can assume triple helical (triplex) structures. Intermolecular triplexes, formed by the addition of a sequence-specific third strand to the major groove of the duplex DNA, have the potential to serve as selective gene regulators. Earlier, we demonstrated efficient triplex formation between the exogenously added triplex-forming oligodeoxyribonucleotides (TFOs) and a specific sequence in the promoter region of the COL1A1 gene. In this study we used a rat model of liver fibrosis, induced by dimethylnitrosamine, to test whether these TFOs prevent liver fibrosis. Our results indicate that both the 25-mer and 18-mer TFOs, specific for the upstream nucleotide sequence from -141 to -165 (relative to the transcription start site) in the 5' end of collagen gene promoter, effectively prevented accumulation of liver collagen and fibrosis. We also observed improvement in liver function tests. However, mutations in the TFO that eliminated formation of triplexes are ineffective in preventing fibrosis. We believe that these TFOs can be used as potential antifibrotic therapeutic molecules.
Koilan
Subramaniyan
S
Department of Molecular Sciences, The University of Tennessee Health Science Center , Memphis, TN, USA.
Hamilton
David
D
Baburyan
Narina
N
Padala
Mythili K
MK
Weber
Karl T
KT
Guntaka
Ramareddy V
RV
D000818:Animals; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004195:Disease Models, Animal; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley
D024042:Collagen Type I; D009838:Oligodeoxyribonucleotides; D004247:DNA
Gut. 2002 Apr;50(4):571-81
11889082
Cancer Biol Ther. 2004 Jan;3(1):4-12
14726654
Curr Med Chem. 2008;15(16):1628-44
18673229
Hepatology. 1999 Mar;29(3):719-27
10051473
Nature. 2008 Jul 24;454(7203):428-35
18650913
Nucleic Acids Res. 1998 Nov 15;26(22):5218-22
9801322
Mol Cell Biol. 1997 Sep;17(9):5201-9
9271398
Am J Gastroenterol. 2008 Jul;103(7):1824-33
18479498
J Clin Invest. 2005 Feb;115(2):209-18
15690074
Clin Chim Acta. 1980 Jun 10;104(2):161-7
7389130
Hepatology. 2007 Mar;45(3):569-78
17326152
J Biol Chem. 1996 Jan 19;271(3):1805-12
8576186
Gastroenterology. 2008 May;134(6):1655-69
18471545
J Mol Biol. 2008 Oct 31;383(1):122-32
18721810
Clin Gastroenterol Hepatol. 2005 Aug;3(8):819-28
16234012
Nucleic Acids Res. 2008 Sep;36(16):5123-38
18676453
Antivir Ther. 2007;12(2):279-83
17503671
Mol Pharm. 2005 May-Jun;2(3):206-17
15934781
Expert Opin Drug Deliv. 2005 Jan;2(1):3-28
16296732
Toxicology. 2001 Jan 2;156(2-3):129-38
11164615
Biochemistry. 2007 Oct 9;46(40):11240-52
17845009
Int J Biochem Cell Biol. 2003 Jan;35(1):22-31
12467644
Exp Cell Res. 2004 Jun 10;296(2):307-16
15149860
Clin Liver Dis. 2008 Nov;12(4):939-62, xi
18984475
Ann N Y Acad Sci. 2005 Nov;1058:151-61
16394134
J Cell Sci. 2005 Apr 1;118(Pt 7):1341-53
15788652
Nucleic Acids Res. 1997 Jun 1;25(11):2182-8
9153319
Int Rev Immunol. 1995;12(2-4):177-85
7650420