Please use this identifier to cite or link to this item:
Title: ACE2 Therapy Using Adeno-associated Viral Vector Inhibits Liver Fibrosis in Mice.
Austin Authors: Mak, Kai Yan;Chin, Ruth;Cunningham, Sharon C;Habib, Miriam R;Torresi, Joseph ;Sharland, Alexandra F;Alexander, Ian E;Angus, Peter W ;Herath, Chandana B
Affiliation: General Medicine
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, the University of Melbourne, Melbourne, Victoria, Australia
Transplantation Research Group, Bosch Institute, The University of Sydney, Sydney, New South Wales, Australi
Infectious Diseases
Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia
Gastroenterology and Hepatology
Issue Date: Sep-2015
Date: 2015-05-23
Publication information: Molecular Therapy : the Journal of the American Society of Gene Therapy 2015; 23(9): 1434-1443
Abstract: Angiotensin converting enzyme 2 (ACE2) which breaks down profibrotic peptide angiotensin II to antifibrotic peptide angiotensin-(1-7) is a potential therapeutic target in liver fibrosis. We therefore investigated the long-term therapeutic effect of recombinant ACE2 using a liver-specific adeno-associated viral genome 2 serotype 8 vector (rAAV2/8-ACE2) with a liver-specific promoter in three murine models of chronic liver disease, including carbon tetrachloride-induced toxic injury, bile duct ligation-induced cholestatic injury, and methionine- and choline-deficient diet-induced steatotic injury. A single injection of rAAV2/8-ACE2 was administered after liver disease has established. Hepatic fibrosis, gene and protein expression, and the mechanisms that rAAV2/8-ACE2 therapy associated reduction in liver fibrosis were analyzed. Compared with control group, rAAV2/8-ACE2 therapy produced rapid and sustained upregulation of hepatic ACE2, resulting in a profound reduction in fibrosis and profibrotic markers in all diseased models. These changes were accompanied by reduction in hepatic angiotensin II levels with concomitant increases in hepatic angiotensin-(1-7) levels, resulting in significant reductions of NADPH oxidase assembly, oxidative stress and ERK1/2 and p38 phosphorylation. Moreover, rAAV2/8-ACE2 therapy normalized increased intrahepatic vascular tone in fibrotic livers. We conclude that rAAV2/8-ACE2 is an effective liver-targeted, long-term therapy for liver fibrosis and its complications without producing unwanted systemic effects.
DOI: 10.1038/mt.2015.92
ORCID: 0000-0002-8212-0887
Journal: Molecular Therapy : the Journal of the American Society of Gene Therapy
PubMed URL: 25997428
Type: Journal Article
Appears in Collections:Journal articles

Show full item record

Page view(s)

checked on Jul 16, 2024

Google ScholarTM


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.