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Acute atorvastatin is hepatoprotective against ischaemia-reperfusion injury in mice by modulating eNOS and microparticle formation

Ajamieh, Hussam; Farrell, Geoffrey; McCuskey, Robert; Yu, Jun; Chu, Eagle; Wong, Heng; Lam, Wesley; Teoh, Narcissus

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Background & Aims: Steatosis accentuates the severity of hepatic ischaemia-reperfusion injury (IRI); 'statins' (HMG-CoA reductase inhibitors) protect the heart and brain against post-ischaemic injury. We tested whether short-term administration of atorvastatin protects fatty livers in obese mice against IRI. Methods: Mice with dietary or genetic simple steatosis (SS) or non-alcoholic steatohepatitis (NASH) were subjected to 60 min partial hepatic ischaemia/24 h reperfusion. Atorvastatin was...[Show more]

dc.contributor.authorAjamieh, Hussam
dc.contributor.authorFarrell, Geoffrey
dc.contributor.authorMcCuskey, Robert
dc.contributor.authorYu, Jun
dc.contributor.authorChu, Eagle
dc.contributor.authorWong, Heng
dc.contributor.authorLam, Wesley
dc.contributor.authorTeoh, Narcissus
dc.date.accessioned2015-12-13T22:16:23Z
dc.identifier.issn1478-3223
dc.identifier.urihttp://hdl.handle.net/1885/70834
dc.description.abstractBackground & Aims: Steatosis accentuates the severity of hepatic ischaemia-reperfusion injury (IRI); 'statins' (HMG-CoA reductase inhibitors) protect the heart and brain against post-ischaemic injury. We tested whether short-term administration of atorvastatin protects fatty livers in obese mice against IRI. Methods: Mice with dietary or genetic simple steatosis (SS) or non-alcoholic steatohepatitis (NASH) were subjected to 60 min partial hepatic ischaemia/24 h reperfusion. Atorvastatin was injected intravenously (5 mg/kg) 1 h before IRI. Liver injury, Toll-like receptor-4 (TLR4), cytokines/chemokines, iNOS/eNOS expression, eNOS activity and thromboxane B2 (TXB2) production were determined. Results: Ischaemia-reperfusion injury was exaggerated by two- to five-fold in SS and NASH compared with lean liver. Atorvastatin pretreatment conferred 70-90% hepatic protection in all animals. Atorvastatin increased post-ischaemic eNOS mRNA/protein and strikingly enhanced eNOS activity (by phospho-eNOS). It also attenuated microparticle (MP) production, NF-κB activation, significantly dampened post-ischaemic thromboxane B2 production, induction of TNF-α, IL-6, MIP-1a, MCP-1, GM-CSF and vascular cell adhesion molecule-1 (VCAM), with a resultant reduction on macrophage and polymorphonuclear neutrophil recruitment. Up-regulation of HMGB1 and TLR4 after IRI was marked in fatty livers; 1 h pretreatment with atorvastatin reduced HMGB1 and TLR4 expression in all livers. Conclusions: Acute (1 h) atorvastatin administration is highly hepatoprotective against IRI in NASH, fatty and lean livers. Key mechanisms include suppression of inflammation by prevention of NF-κB activation, microvascular protection via eNOS activation and suppression of TXB2 and MP release. Short-term intravenous statin treatment is a readily available and effective preventive agent against hepatic IRI, irrespective of obesity and fatty liver disease, and merits clinical trials in at-risk patients.
dc.publisherBlackwell Publishing Inc.
dc.sourceLiver International
dc.titleAcute atorvastatin is hepatoprotective against ischaemia-reperfusion injury in mice by modulating eNOS and microparticle formation
dc.typeJournal article
local.description.notesImported from ARIES
dc.date.issued2015
local.identifier.absfor111700 - PUBLIC HEALTH AND HEALTH SERVICES
local.identifier.absfor110300 - CLINICAL SCIENCES
local.identifier.absfor111200 - ONCOLOGY AND CARCINOGENESIS
local.identifier.ariespublicationa383154xPUB2435
local.type.statusPublished Version
local.contributor.affiliationAjamieh, Hussam, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationFarrell, Geoffrey, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationMcCuskey, Robert, University of Arizona
local.contributor.affiliationYu, Jun, Li KaShing Institute of Health Sciences
local.contributor.affiliationChu, Eagle, Li KaShing Institute of Health Sciences
local.contributor.affiliationWong, Heng, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLam, Wesley, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationTeoh, Narcissus, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.identifier.doi10.1111/liv.12827
dc.date.updated2015-12-11T07:25:48Z
local.identifier.scopusID2-s2.0-84927126957
CollectionsANU Research Publications

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