title: Pre-treatment of a single high-dose of atorvastatin provided cardioprotection in different ischaemia/reperfusion models via activating mitochondrial KATP channel.
abstract: A number of clinical trials have shown that a high loading dose of atorvastatin (Ator) within 24h before percutaneous coronary intervention (PCI) exerts protective effects on the cardiovascular system. However, the potential mechanisms regarding this rapid benefit of Ator remain elusive. Our study introduced three different ischaemia/reperfusion (I/R) models: I/R in vivo, I/R in vitro and oxygen-glucose deprivation/recovery (OGD/R) in primary neonatal rat cardiac myocytes to observe the protective effect of a single loading dose of Ator pre-treatment and further to explore the potential mechanisms of this protective effect with confocal laser scanning microscopy, flow cytometry, biochemical and morphology methods. We found that the pre-treatment of high-dose Ator decreased the cardiac injury and maintained the integrity of mitochondria in all three of the I/R models, which was similar to ischaemic pre-conditioning (IPC). We used the mitochondrial K(ATP) channels (mitoKATP channels) inhibitor 5-hydroxydecanoate (5-HD) and the mitochondrial permeability transition pore (mPTP) opener lonidamine (LND) to analyse the underlying mechanisms. The results showed that the pre-treatment of Ator significantly decreased I/R-induced injury, and maintained the functional integrity of mitochondria through alleviating Ca(2+) overload, reactive oxygen species burst, inhibiting the opening of mPTP and preventing mitochondrial membrane potential (ΔΨm) depolarisation. The present results demonstrated that a single dose of Ator might protect the myocardium from I/R-induced injury by inhibiting the mPTP opening through activating the mitoKATP channels. This result may contribute toward the development of novel strategies for clinical cardioprotection against I/R injury.
authors: Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China; Department of Respiration, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
authors: Zhifang
authors: Z
authors: Zhao
authors: Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China. Electronic address: weicuicn@126.com.
authors: Wei
authors: W
authors: Cui
authors: Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.
authors: Hailin
authors: H
authors: Zhang
authors: Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.
authors: Haixia
authors: H
authors: Gao
authors: Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
authors: Xuze
authors: X
authors: Li
authors: Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
authors: Yuanyuan
authors: Y
authors: Wang
authors: Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
authors: Haijuan
authors: H
authors: Hu
authors: The National Institute for The Control of Pharmaceutical and Biological Products, Beijing, China.
authors: Bo
authors: B
authors: Li
mesh_terms: D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012306:Risk
chemical_list: D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D000069059:Atorvastatin; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D010100:Oxygen; D002118:Calcium
keywords: Atorvastatin; Cardioprotection; Ischaemic pre-conditioning; Mitochondrial KATP channels; Mitochondrial permeability transition pore