title: Sulindac confers high level ischemic protection to the heart through late preconditioning mechanisms.
abstract: We have recently shown that sulindac, an anti-inflammatory drug, enhances the killing of cancer cells, but not normal cells, under conditions of oxidative stress, by mechanisms unrelated to its cyclooxygenase (COX) inhibition. To further study the protective effect of sulindac on cells exposed to oxidative stress, we have investigated the effect of sulindac on rat cardiac myocytes subjected to hypoxia/reoxygenation, as well as in a Langendorff model of myocardial ischemia. Low levels of sulindac could protect cardiac myocytes against cell death due to hypoxia/reoxygenation. In the Langendorff model sulindac provided significant protection against cell death, when the drug was fed to the animals before the removal of the heart for the Langendorff procedure. The results indicate that the primary protective effect of sulindac in these experiments does not involve its role as a COX inhibitor. Numerous signaling pathways have been implicated in myocardial protective mechanisms, many of which involve fluctuations in reactive oxygen species (ROS) levels. The results suggest that low levels of sulindac can induce a preconditioning response, triggered by ROS, to protect cardiac tissues against oxidative damage. Blocking of preconditioning pathways by administration of the PKC blocker chelerythrine abrogated the ischemic protection afforded by sulindac. Secondly, after feeding of sulindac, two end-effectors of preconditioning, inducible nitric oxide synthase and heat shock protein 27, were found to be markedly induced in the heart, dependent on PKC. These results suggest that sulindac may have therapeutic potential as a preconditioning agent.
authors.affiliation: College of Biomedical Science, and Center for Molecular Biology and Biotechnology, Florida Atlantic University, Boca Raton, FL 33431, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Moench
authors.forename: Howard
authors.initials: H
authors.lastname: Prentice
authors.forename: Zach
authors.initials: Z
authors.lastname: Rickaway
authors.forename: Herbert
authors.initials: H
authors.lastname: Weissbach
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019610:Cytoprotection; D004195:Disease Models, Animal; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D019157:Ischemic Preconditioning, Myocardial; D017202:Myocardial Ischemia / Q000517:prevention & control*; D009206:Myocardium; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D055551:HSP27 Heat-Shock Proteins; D017382:Reactive Oxygen Species; D013467:Sulindac; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C