Submitted on February 4, 2009
Revised on April 3, 2009
Accepted on April 15, 2009
Portal pressure responses and angiotensin peptide production in rat liver are determined by relative activity of angiotensin converting enzyme (ACE) and ACE2
Chandana B Herath1*, John S Lubel2, Zhiyuan Jia1, Elena Velkoska1, David Casley1, Lindsay Brown3, Chris Tikellis4, Louise M Burrell1, and Peter W Angus5
1 University of Melbourne
2 Austin Hospital
3 The University of Queensland
4 Baker Heart Research Institute
5 Austin Health
* To whom correspondence should be addressed. E-mail: cherath{at}unimelb.edu.au.
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, 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 catalysed 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.
