title: Portal pressure responses and angiotensin peptide production in rat liver are determined by relative activity of ACE and ACE2.
abstract: Angiotensin converting enzyme (ACE) 2 activity and angiotensin-(1-7) [Ang-(1-7)] levels are increased in experimental cirrhosis; however, the pathways of hepatic Ang-(1-7) production have not been studied. This study investigated the role of ACE2, ACE, and neutral endopeptidase (NEP) in the hepatic formation of Ang-(1-7) from angiotensin I (Ang I) and Ang II and their effects on portal resistance. Ang I or Ang II were administered to rat bile duct ligated (BDL) and control livers alone and in combination with the ACE inhibitor lisinopril, the ACE and NEP inhibitor omapatrilat, or the ACE2 inhibitor MLN4760 (n = 5 per group). BDL markedly upregulated ACE, ACE2, and NEP. Ang-(1-7) was produced from Ang II in healthy and in BDL livers and was increased following ACE inhibition and decreased by ACE2 inhibition. In contrast, Ang-(1-7) production from Ang I was minimal and not affected by ACE or NEP inhibition. Surprisingly, ACE2 inhibition in BDLs dramatically increased Ang-(1-7) production from Ang I, an effect abolished by ACE2/NEP inhibition. Ang II and Ang I induced greater portal pressure increases in BDL livers than controls. The effects of Ang I were closely correlated with Ang II production and were strongly attenuated by both ACE and ACE/NEP inhibition. These findings show that the major substrate for hepatic production of Ang-(1-7) is Ang II and this is catalyzed by ACE2. Ang I is largely converted to Ang II by ACE, and net conversion of Ang I to Ang-(1-7) is small. NEP has the ability to generate large amounts of Ang-(1-7) in the BDL liver from Ang I only when ACE2 activity is greatly decreased or inhibited.
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Repatriation Hospital, Heidelberg Heights, Victoria, Australia. cherath@unimelb.edu.au
authors.forename: Chandana B
authors.initials: CB
authors.lastname: Herath
authors.forename: John S
authors.initials: JS
authors.lastname: Lubel
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Jia
authors.forename: Elena
authors.initials: E
authors.lastname: Velkoska
authors.forename: David
authors.initials: D
authors.lastname: Casley
authors.forename: Lindsay
authors.initials: L
authors.lastname: Brown
authors.forename: Chris
authors.initials: C
authors.lastname: Tikellis
authors.forename: Louise M
authors.initials: LM
authors.lastname: Burrell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Angus
mesh_terms: D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000809:Angiotensins / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D003135:Common Bile Duct / Q000601:surgery; D015971:Gene Expression Regulation, Enzymologic; D007093:Imidazoles / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008026:Ligation; D017706:Lisinopril / Q000494:pharmacology; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D017082:Portal Pressure / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000235:genetics; D012720:Severity of Illness Index; D013841:Thiazepines / Q000494:pharmacology; D013997:Time Factors; D014655:Vascular Resistance
chemical_list: C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D013841:Thiazepines; D000804:Angiotensin II; C106266:omapatrilat; D000803:Angiotensin I; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D015260:Neprilysin; D007930:Leucine; C118790:angiotensin I (1-7)