Basic Research
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. May 7, 2008; 14(17): 2731-2739
Published online May 7, 2008. doi: 10.3748/wjg.14.2731
Mitochondrial protection by low doses of insulin-like growth factor-Iin experimental cirrhosis
Raquel Pérez, María García-Fernández, Matías Díaz-Sánchez, Juan E Puche, Gloria Delgado, Marian Conchillo, Jordi Muntané, Inma Castilla-Cortázar
Raquel Pérez, Matías Díaz-Sánchez, Marian Conchillo, Departments of Human Physiology and Internal Medicine, University of Navarra, Pamplona 31080, Spain
María García-Fernández, Juan E Puche, Gloria Delgado, Inma Castilla-Cortázar, Department of Medical Physiology, School of Medicine, University of Málaga, Málaga 29080, Spain
Juan E Puche, Inma Castilla-Cortázar, Department of Medical Physiology, School of Medicine, University USP-CEU, Madrid 28668, Spain
Jordi Muntané, Department of Internal Medicine, Liver Unit, University of Córdoba, Córdoba 14004, Spain
Author contributions: Pérez R worked on mitochodrial function tests, in vivo treatments; Díaz-Sánchez M worked on TUNEL assay; García-Fernández M contributed to analitical and mitochondrial function tests; Puche JE worked on experimental design and Western blot; Muntané J contributed to Western blot for caspase; Delgado G analyse the data; Conchillo M designed the study; Castilla-Cortázar I contributed to the histology, experimental design, in vivo treatment, statistical analysis and wrote the paper.
Correspondence to: Inma Castilla de Cortázar Larrea, MD, Department of Medical Physiology, School of Medicine, University CEU-USP, Boadilla del Monte, Madrid 28668, Spain.
Telephone: +34-91-3724765
Fax: +34-91-3724008
Received: November 1, 2007
Revised: February 16, 2008
Published online: May 7, 2008

AIM: To characterize the mitochondrial dysfunction in experimental cirrhosis and to study whether insulin-like growth factor-I(IGF-I) therapy (4 wk) is able to induce beneficial effects on damaged mitochondria leading to cellular protection.

METHODS: Wistar rats were divided into three groups: Control group, untreated cirrhotic rats and cirrhotic rats treated with IGF-Itreatment (2 &mgr;g/100 g bw/d). Mitochondrial function was analyzed by flow cytometry in isolated hepatic mitochondria, caspase 3 activation was assessed by Western blot and apoptosis by TUNEL in the three experimental groups.

RESULTS: Untreated cirrhotic rats showed a mitochondrial dysfunction characterized by a significant reduction of mitochondrial membrane potential (in status 4 and 3); an increase of intramitochondrial reactive oxigen species (ROS) generation and a significant reduction of ATPase activity. IGF-Itherapy normalized mitochondrial function by increasing the membrane potential and ATPase activity and reducing the intramitochondrial free radical production. Activity of the electron transport complexes Iand III was increased in both cirrhotic groups. In addition, untreated cirrhotic rats showed an increase of caspase 3 activation and apoptosis. IGF-Itherapy reduced the expression of the active peptide of caspase 3 and resulted in reduced apoptosis.

CONCLUSION: These results show that IGF-Iexerts a mitochondrial protection in experimental cirrhosis leading to reduced apoptosis and increased ATP production.

Keywords: Insulin-like growth factor-I, Cirrhosis, Mitochondrial protection, Caspases, Apoptosis, Oxidative damage