ABSTRACT
AIMS: Glycogen synthase kinase-3ß (GSK-3ß) 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-3ß, 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. CONCLUSION: Rosuvastatin prevents myocardial ischemia-reperfusion injury by inducing phosphorylation of PI3K-Akt and GSK-3ß, preventing oxidative stress and subsequent inhibition of mPTP opening.
Subject(s)
Antioxidants/pharmacology , Glycogen Synthase Kinase 3 beta/metabolism , Mitochondria, Heart/drug effects , Mitochondrial Membrane Transport Proteins/antagonists & inhibitors , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Myocytes, Cardiac/drug effects , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , Rosuvastatin Calcium/pharmacology , Animals , Antioxidants/toxicity , Calcium Signaling/drug effects , Cytoprotection , Disease Models, Animal , Dose-Response Relationship, Drug , Isolated Heart Preparation , Male , Mitochondria, Heart/enzymology , Mitochondria, Heart/pathology , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Myocardial Infarction/enzymology , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/enzymology , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Rats, Wistar , Rosuvastatin Calcium/toxicity , Time Factors , Ventricular Function, Left/drug effectsABSTRACT
Cyclosporine-A (CsA) is an immunosuppressant agent that has shown effectiveness as a neuroprotective drug; however, it does not readily cross the blood-spinal cord barrier (BSCB), which constrains the clinical applications of CsA for the treatment of spinal cord injury (SCI). Our group recently tested the ability of novel polyethylene glycol (PEG)-transactivating-transduction protein (TAT)-modified CsA-loaded cationic multifunctional polymeric liposome-poly(lactic-co-glycolic acid) (PLGA) core/shell nanoparticles (PLGA/CsA NPs) to transport and deliver CsA across the BSCB to treat SCI. The PLGA/CsA NPs were successfully constructed. In vitro drug release studies have demonstrated that the sustained release of CsA from PLGA/CsA NPs occurs over â¼25 h. The in vivo study presented here showed that injured animals that received PLGA/CsA NPs through the tail vein, exhibited a significant up-regulation of growth-associated protein-43 (GAP-43) expression and an increased number of GAP-43-stained neurons compared with animals that received CsA or the vehicle alone. The improvement in neurological function was also evaluated by the Basso-Beattie-Bresnahan (BBB) open-field test. Moreover, fluorescein isothiocyanate (FITC)-attached PLGA/CsA NPs were successfully aggregated in the intact spinal cord 4 h after injection. Our data suggest that PLGA/CsA NPs have the potential for use as a new treatment method for SCI.
