Glycolipid RC-552 induces delayed preconditioning-like effect via iNOS-dependent pathway in mice.
We recently demonstrated that monophosphoryl lipid A (MLA)-induced delayed cardioprotection is mediated by inducible nitric oxide synthase (iNOS) in mice. In the present study, we determined whether RC-552, a novel synthetic glycolipid related in chemical structure to MLA, could afford similar protection. Adult mice were pretreated with vehicle or RC-552 (350 microg/kg ip, n = 7 mice/group) 24 h before global ischemia and reperfusion in a Langendorff isolated, perfused heart model. A group of RC-552-treated mice received S-methylisothiourea (SMT), a selective inhibitor of iNOS (3 mg/kg ip), 30 min before heart perfusion. Myocardial infarct size was significantly reduced from 19.2 +/- 2.0% in vehicle to 8.2 +/- 2.9% in RC-552 group (P < 0.05). Treatment with SMT abolished RC-552-induced reduction in infarct size (20.0 +/- 3.9%). In addition, RC-552 failed to reduce infarct size in isolated hearts from iNOS knockout mice (27.1 +/- 2.8%) compared with that in hearts from control knockout mice without drug treatment (22.9 +/- 5.4%). Acute buffer perfusion with RC-552 (0.1, 1.0, or 2.5 microg/ml) for 8 min immediately before ischemia-reperfusion did not reduce infarct size significantly. We concluded that RC-552 induces delayed cardioprotection via an iNOS-dependent pathway.
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Division of Cardiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Salloum
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Tekin
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Jarrett
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Kukreja
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RC
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006017:Glycolipids / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D019194:Ischemic Preconditioning / Q000379:methods*; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000503:physiopathology; D015425:Myocardial Reperfusion; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D006017:Glycolipids; D007550:Isothiuronium; C402894:RC 552; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C027744:S-methylisothiopseudouronium