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Title: Adenoviral delivery of dominant-negative transforming growth factor ? type II receptor up-regulates transcriptional repressor SKI-like oncogene, decreases matrix metalloproteinase 2 in hepatic stellate cell and prevents liver fibrosis in rats
Author: Marquez-Aguirre, A.
Sandoval-Rodriguez, A.
Gonzalez-Cuevas, J.
Bueno-Topete, M.
Navarro-Partida, J.
Arellano-Olivera, I.
Lucano-Landeros, S.
Armendariz-Borunda, J.
Issue Date: 2009
Abstract: Background: Dominant-negative transforming growth factor ? type II receptor (T?RII?cyt) is a protein that blocks transforming growth factor (TGF-?) signaling. Because the consequences of blocking TGF-? have not been completely elucidated in liver fibrosis, we analysed the effects of adenoviral delivery of T?RII?cyt on profibrogenic genes and matrix metalloproteinase (MMP) proteins, as well as on TGF-? signal repressor SKI-like oncogene (SnoN), in cultured hepatic stellate cells (HSCs) and in a rat model of liver fibrosis. Methods: To induce liver fibrosis, rats were treated with thioacetamide for 7 weeks and administrated once with Ad-T?RII?cyt or Ad-?gal through the iliac vein. Fibrosis was measured by morphometric analysis. We evaluated SnoN by western blot, immunocytochemistry and immunohistochemistry; MMP activity was determined by zymography and profibrogenic gene expression by the real-time reverse transcriptase-polymerase chain reaction in cultured HSCs and liver tissue. Results: Profibrogenic gene expression of collagen ?1 (I), TGF-?1, platelet-derived growth factor-B, plasminogen activator inhibitor (PAI)-1, tissue inhibitor of matrix metalloproteinase-1 and MMP-2 was down-regulated; whereas MMP-3 was over-expressed in response to Ad-T?RII?cyt in HSCs. Moreover, zymography assays corroborated MMP-2 and MMP-3 changes in activity. Surprisingly, anti-TGF-? molecular intervention increased nuclear SnoN in HSCs. In vivo, Ad-T?RII?cyt reduced liver fibrosis, increased nuclear SnoN in sinusoidal cells, and also produced significant suppression in collagen ?1 (I), TGF-?1, PAI-1, MMP-2 and over-expression in MMP-3 in thioacetamide-intoxicated animals. Conclusions: The results obtained in the present study suggest that the molecular mechanism for the blocking effects of Ad-T?RII?cyt in TGF-? signaling acts via up-regulation of the transcriptional repressor SnoN, which antagonizes TGF-? signaling (TGF-?/ Smad-pathway inhibitor). Consequently, profibrogenic genes are down-regulated. Copyright Zapotitlán 2009 John Wiley & Sons, Ltd.
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