title: Rosuvastatin postconditioning protects isolated hearts against ischemia-reperfusion injury: The role of radical oxygen species, PI3K-Akt-GSK-3β pathway, and mitochondrial permeability transition pore.
abstract: OBJECTIVE
  Glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore (mPTP) play an important role in myocardial ischemia-reperfusion injury. The aim of this study was to investigate whether postconditioning with rosuvastatin is able to reduce myocardial ischemia-reperfusion injury and clarify the potential mechanisms.
  
  
  METHODS
  Isolated rat hearts underwent 30 minutes of ischemia and 60 minutes of reperfusion in the presence or absence of rosuvastatin (1-50 nmol/L). The activity of signaling pathway was determined by Western blot analysis, and Ca2+-induced mPTP opening was assessed by the use of a potentiometric method.
  
  
  RESULTS
  Rosuvastatin significantly reduced myocardial infarct size and improved cardiac function at 5 and 10 nmol/L. Protection disappeared at higher concentration and reverted to increased damage at 50 nmol/L. At 5 nmol/L, rosuvastatin increased the phosphorylation of protein kinase B (Akt) and GSK-3β, concomitant with a higher Ca2+load required to open the mPTP. Rosuvastatin postconditioning also significantly increased superoxide dismutase activity and reduced malondialdehyde and radical oxygen species level. LY294002, phosphatidylinositol-3-kinase (PI3K) inhibitors, abolished these protective effects of rosuvastatin postconditioning.
  
  
  CONCLUSIONS
  Rosuvastatin prevents myocardial ischemia-reperfusion injury by inducing phosphorylation of PI3K-Akt and GSK-3β, preventing oxidative stress and subsequent inhibition of mPTP opening.
authors: Department of Cardiology, Tianjin Medical University, Tianjin Chest Hospital, Tianjin, China.
authors: Chun-Wei
authors: CW
authors: Liu
authors: Department of Diagnostic Ultrasound, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
authors: Fan
authors: F
authors: Yang
authors: Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin, China.
authors: Shi-Zhao
authors: SZ
authors: Cheng
authors: Department of Cardiology, Tianjin Medical University, Tianjin Chest Hospital, Tianjin, China.
authors: Yue
authors: Y
authors: Liu
authors: Department of Cardiology, Tianjin Medical University, Tianjin Chest Hospital, Tianjin, China.
authors: Liang-Hui
authors: LH
authors: Wan
authors: Department of Cardiology, Tianjin Medical University, Tianjin Chest Hospital, Tianjin, China.
authors: Hong-Liang
authors: HL
authors: Cong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000633:toxicity; D020013:Calcium Signaling / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D000067268:Isolated Heart Preparation; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000068718:Rosuvastatin Calcium / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000975:Antioxidants; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D000068718:Rosuvastatin Calcium; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt
keywords: 
  ROS
  ; GSK-3β; MPTP opening; PI3K-Akt; Rosuvastatin