title: ACE2 Therapy Using Adeno-associated Viral Vector Inhibits Liver Fibrosis in Mice.
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.
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Kai Y
authors.initials: KY
authors.lastname: Mak
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, the University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ruth
authors.initials: R
authors.lastname: Chin
authors.affiliation: Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia.
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Cunningham
authors.affiliation: Transplantation Research Group, Bosch Institute, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Habib
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, the University of Melbourne, Melbourne, Victoria, Australia.|Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Joseph
authors.initials: J
authors.lastname: Torresi
authors.affiliation: Transplantation Research Group, Bosch Institute, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Sharland
authors.affiliation: Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Alexander
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.|Department of Gastroenterology and Hepatology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Angus
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Chandana B
authors.initials: CB
authors.lastname: Herath
mesh_terms: D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D055166:Hepatic Stellate Cells / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D015227:Lipid Peroxidation / Q000235:genetics; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008111:Liver Function Tests; D020935:MAP Kinase Signaling System; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D000804:Angiotensin II; D000803:Angiotensin I; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D008729:Methoxamine