title: Blockade of the renin-angiotensin system improves the early stages of liver regeneration and liver function.
abstract: BACKGROUND
  Partial hepatectomy is the preferred option for selected patients with colorectal cancer liver metastases (CRCLM). Sufficient liver regeneration (LR) is essential for a successful outcome in these patients. The blockade of the renin-angiotensin system (RAS) reduces the growth of several tumor types. The RAS also acts as a regulator of liver fibrosis and potentially LR. The angiotensin-converting enzyme (ACE) inhibitor, captopril, significantly inhibits the growth of CRCLM, but its effect on LR remains undefined.
  
  
  METHODS
  After 70% of partial hepatectomy, mice were randomly assigned to control or captopril-treated groups. LR was measured by liver-to-body weight ratio on days 1, 2, 4, 6, and 8. Hepatocyte proliferation, apoptosis and cell size, hepatic stellate cell (HSC) count, and sinusoidal endothelial cell density were quantified. Matrix metalloproteinase 9 (MMP-9) protein levels, liver injury markers, and RAS messenger RNA levels were also determined.
  
  
  RESULTS
  At day 2, captopril increased liver-to-body weight ratio (56.5 ± 1.7 captopril versus 49.3 ± 2.4 control, P = 0.027). This was associated with increased HSC count (65.4 ± 4.8 cells per 100,000 μm(2), 48.7 ± 2.3, P = 0.007) and MMP-9 levels (0.68 ± 0.12 AU, 0.12 ± 0.04, P = 0.014). The messenger RNA levels of angiotensin-converting enzyme (P = 0.045) and angiotensin 1 receptor (P = 0.039) were reduced by captopril at day 2.
  
  
  CONCLUSIONS
  Captopril enhanced early LR. This effect was associated with increased HSC numbers and MMP-9 protein, whereas hepatocyte proliferation was lower than controls. Captopril may provide a beneficial treatment option for the management of patients with CRCLM.
authors.affiliation: Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. shir_lin@hotmail.com
authors.forename: Shir Lin
authors.initials: SL
authors.lastname: Koh
authors.forename: Eleanor
authors.initials: E
authors.lastname: Ager
authors.forename: Cathy
authors.initials: C
authors.lastname: Malcontenti-Wilson
authors.forename: Vijayaragavan
authors.initials: V
authors.lastname: Muralidharan
authors.forename: Christopher
authors.initials: C
authors.lastname: Christophi
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002216:Captopril / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D023421:Models, Animal; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D020780:Matrix Metalloproteinase 9