Administration of naked plasmid encoding hepatic stimulator substance by hydrodynamic tail vein injection protects mice from hepatic failure by suppressing the mitochondrial permeability transition.

Abstract

Acute liver failure is a devastating illness of various causes with considerable mortality. Hepatic stimulator substance (HSS) has been suggested for use as a protective agent against acute hepatic injury induced by chemical poisons because it has a variety of biological activities. However, the mechanism whereby HSS protects against hepatotoxins is poorly understood. In this study, we established a hepatic gene transfer system via hydrodynamic tail vein injection to deliver a naked plasmid containing the human HSS gene (hHSS) and analyzed HSS-mediated protection of the liver during fulminant hepatic failure (FHF) induced by D-galactosamine (D-gal) and lipopolysaccharide (LPS). The results showed that the reporter gene, enhanced green fluorescent protein, was efficiently expressed in the liver of BALB/c mice. Hydrodynamic-based transfection of hHSS yielded a 70% survival rate compared with 36.7% for the control group at 24 h after D-gal/LPS treatment. In addition, hHSS expression preserved liver morphology and function. It is noteworthy that hHSS hydrodynamic-based transfer ameliorated indices of the mitochondrial permeability transition (MPT) resulting from the toxic effects of d-gal/LPS on the liver such as mitochondrial swelling, mitochondrial transmembrane potential disruption, and cytochrome c translocation. Furthermore, mitochondrial morphology and ATP levels were maintained in hHSS-administered mice. HSS-mediated protection was similar to that observed with the MPT inhibitor N-methyl-4-isoleucine-cyclosporin (NIM811), indicating a possible role for HSS in the regulation of MPT. In conclusion, a single dose of hHSS plasmid protected mice from FHF, and this hepatoprotective effect seemed to correlate with the inhibition of MPT.

• Authors: Shenglan Li, Zuoqing Tang, Hao Yu, Wen Li, Ying Jiang, Yutong Wang, Wei An
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 338 Issue 3 Pg. 750-7 (Sep 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21613410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intercellular Signaling Peptides and Proteins
• Peptides
• hepatic stimulator substance
• Green Fluorescent Proteins
• Cyclosporine
• Adenosine Triphosphate
• Cytochromes c
• (melle-4)cyclosporin

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Blotting, Western
• Cyclosporine (pharmacology)
• Cytochromes c (metabolism)
• Cytosol (drug effects, metabolism)
• Energy Metabolism (drug effects)
• Genetic Therapy (methods)
• Green Fluorescent Proteins
• Humans
• Injections, Intravenous
• Intercellular Signaling Peptides and Proteins
• Liver (metabolism)
• Liver Failure, Acute (pathology, prevention & control)
• Male
• Membrane Potentials (drug effects)
• Mice
• Mice, Inbred BALB C
• Mitochondria, Liver (pathology, physiology)
• Mitochondrial Swelling (drug effects)
• Peptides (genetics, metabolism)
• Permeability
• Plasmids (administration & dosage, genetics)
• Regional Blood Flow (physiology)
• Tail (blood supply)
• Veins (physiology)