title: Effects of different doses of statins on liver regeneration through angiogenesis and possible relation between these effects and acute phase responses.
abstract: BACKGROUND
  We examined the effects of two doses of statins on liver regeneration through angiogenesis and its possible relation to acute phase responses.
  
  
  METHODS
  Seventy-two rats were randomly divided into three groups: controls; low-dose atorvastatin (0.5 mg/kg/d); high-dose atorvastatin (2.5 mg/kg/d). Statin was administered daily by oral gavage for 7 days. After atorvastatin treatment, all animals in the three groups underwent 70% hepatectomy. Thereafter animals were subdivided into three subgroups, to evaluate the characteristics of liver regeneration proliferating cell nuclear antigen (PCNA), angiogenesis (KDR/Flk-1 [vascular endothelial growth factor-2]) and acute phase response (serum interleukin [IL]-6) at 12, 24, and 72 hours.
  
  
  RESULTS
  At the 24 hours posthepatectomy, low-dose compared with high-dose atorvastatin increased liver regeneration (P = .004) and angiogenic responses compared also to controls (P = .026 and P = .059). However, there appeared no difference in IL-6 expression (P = .159). At the 72 hours posthepatectomy, low-dose atorvastatin treatment increased liver regeneration compared with controls (P = .047), but it showed no significant difference from the high-dose treatment (P = .109). Low doses of statin increased angiogenic responses compared with both control and high-dose animals (P = .016 and P = .002). Moreover, the high-dose group displayed decreased angiogenic responses compared with the control group (P = .044). Serum IL-6 expression was significantly greater among both low- and high-dose groups compared with controls (P = .005 and P = .003, respectively).
  
  
  CONCLUSIONS
  Low-dose statin treatment increased KDR/Flk-1-dependent angiogenesis, which resulted in an increased regeneration response. In contrast, high-dose statin therapy decreased angiogenesis without affecting long-term regeneration responses. Finally, statin therapy may contribute to liver regeneration due to prolonged IL-6 expression independent of statin doses.
authors.affiliation: Department of General Surgery, Faculty of Medicine, Baskent University, Ankara, Turkey. temercolakoglu@yahoo.com
authors.forename: T
authors.initials: T
authors.lastname: Colakoglu
authors.forename: T Z
authors.initials: TZ
authors.lastname: Nursal
authors.forename: A
authors.initials: A
authors.lastname: Ezer
authors.forename: F
authors.initials: F
authors.lastname: Kayaselcuk
authors.forename: A
authors.initials: A
authors.lastname: Parlakgumus
authors.forename: S
authors.initials: S
authors.lastname: Belli
authors.forename: H
authors.initials: H
authors.lastname: Karakayali
authors.forename: M
authors.initials: M
authors.lastname: Haberal
mesh_terms: D000210:Acute-Phase Reaction / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D000069059:Atorvastatin; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006498:Hepatectomy; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D018809:Proliferating Cell Nuclear Antigen; D011758:Pyrroles; D000069059:Atorvastatin; D040301:Vascular Endothelial Growth Factor Receptor-2