title: Protection by Nitric Oxide Donors of Isolated Rat Hearts Is Associated with Activation of Redox Metabolism and Ferritin Accumulation.
abstract: Preconditioning (PC) procedures (ischemic or pharmacological) are powerful procedures used for attaining protection against prolonged ischemia and reperfusion (I/R) injury, in a variety of organs, including the heart. The detailed molecular mechanisms underlying the protection by PC are however, complex and only partially understood. Recently, an 'iron-based mechanism' (IBM), that includes de novo ferritin synthesis and accumulation, was proposed to explain the specific steps in cardioprotection generated by IPC. The current study investigated whether nitric oxide (NO), generated by exogenous NO-donors, could play a role in the observed IBM of cardioprotection by IPC. Therefore, three distinct NO-donors were investigated at different concentrations (1-10 μM): sodium nitroprusside (SNP), 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). Isolated rat hearts were retrogradely perfused using the Langendorff configuration and subjected to prolonged ischemia and reperfusion with or without pretreatment by NO-donors. Hemodynamic parameters, infarct sizes and proteins of the methionine-centered redox cycle (MCRC) were analyzed, as well as cytosolic aconitase (CA) activity and ferritin protein levels. All NO-donors had significant effects on proteins involved in the MCRC system. Nonetheless, pretreatment with 10 μM SNAP was found to evoke the strongest effects on Msr activity, thioredoxin and thioredoxin reductase protein levels. These effects were accompanied with a significant reduction in infarct size, increased CA activity, and ferritin accumulation. Conversely, pretreatment with 2 μM SIN-1 increased infarct size and was associated with slightly lower ferritin protein levels. In conclusion, the abovementioned findings indicate that NO, depending on its bio-active redox form, can regulate iron metabolism and plays a role in the IBM of cardioprotection against reperfusion injury.
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebrew University of Jerusalem, Jerusalem, Israel.|Anesthesiology and Critical Care Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Hilbert
authors.initials: H
authors.lastname: Grievink
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebrew University of Jerusalem, Jerusalem, Israel.|Department of Radiology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Galina
authors.initials: G
authors.lastname: Zeltcer
authors.affiliation: Anesthesiology and Critical Care Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Drenger
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebrew University of Jerusalem, Jerusalem, Israel.|Electron Microscopy Unit, The Core Research Facility, Hebrew University, Jerusalem, Israel.
authors.forename: Eduard
authors.initials: E
authors.lastname: Berenshtein
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Mordechai
authors.initials: M
authors.lastname: Chevion
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007501:Iron / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008715:Methionine / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects*; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats
chemical_list: D020030:Nitric Oxide Donors; D020011:Protective Agents; D005293:Ferritins; D008715:Methionine; D007501:Iron; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D000154:Aconitate Hydratase