The heat shock protein 90 inhibitor, 17-AAG, attenuates thioacetamide induced liver fibrosis in mice

详细信息    查看全文

• 作者：Nashwa M. Abu-Elsaad^a ; ^{nosha.samaa@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Marwa S. Serrya^a ; ^{marwa.sereya@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Amr M. El-Karef^b ; ^{aelkaref@yahoo.com" class="auth_mail" title="E-mail the corresponding author} ; Tarek M. Ibrahim^a ; ^{tarekmoss@yahoo.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：17-AAG ; 17-N-Allylamino-17-demethoxygeldanamycin ; Col1A1 ; collagen-1-alpha1 ; GSH ; reduced glutathione ; HSC ; hepatic stellate cells ; Hsp ; heat shock protein ; SMA ; smooth muscle actin ; TIMP ; tissue inhibitor metalloproteinase
• 刊名：Pharmacological Reports
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：68
• 期：2
• 页码：275-282
• 全文大小：2427 K

文摘

Heat shock protein 90 (Hsp90) is proposed to be involved in liver disorders. This study was conducted to test effect of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90, on attenuating thioacetamide induced liver fibrosis in vivo.

Methods

Four groups of Swiss albino male mice (CD-1 strain) were used as follows: control group; thioacetamide group (received 100 mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks); thioacetamide plus 17-AAG groups (received 100 mg/kg thioacetamide, ip injection, 3 times/week for 8 weeks plus 25 or 50 mg/kg 17-AAG, ip injection, 5 days/week along the last 4 weeks). Fibrosis was quantified by measuring hydroxyproline level and by morphometry and oxidative stress biomarkers were assigned. Relative hepatic mRNA expressions of α-smooth muscle actin (α-SMA), collagen-1-alpha-1 (Col1A1) and tissue inhibitor metalloproteinase-1 (TIMP-1) mRNAs were measured by RT-PCR. Levels of the apoptotic markers caspase-3, factor related apoptosis (Fas) and Hsp-90 were assigned in tissue homogenate.

Results

17-AAG (50 mg/kg) significantly decreased fibrosis percentage significantly (p < 0.001, 0.05) compared to thioaceatmide and 25 mg/kg, respectively. Malondialdehyde, Hsp90, α-SMA, Col1A1 and TIMP-1 expression levels were significantly reduced (p < 0.05) by the inhibitor large dose. Levels of GSH, caspase-3 and Fas were markedly (p < 0.001) increased in the group received 17-AAG (50 mg/kg) compared to other groups.

Conclusion

The Hsp90 inhibitor, 17-AAG, can attenuate thioacetamide hepatotoxicity through oxidative stress counterbalance, reducing stellate cells activity and inducing apoptosis.