title: Restoration of sirt1 function by pterostilbene attenuates hypoxia-reoxygenation injury in cardiomyocytes.
abstract: Restoration of blood supply to ischemic myocardium causes cardiomyocyte damage, a process known as ischemia-reperfusion injury. Excess reactive oxygen species and intracellular calcium contribute to cell damage but the involvement of sirt1, a versatile protein deacetylase in reperfusion-induced cell damage remains unknown. Here, we found that hypoxia-reoxygenation, an in vitro model of ischemia-reperfusion injury, induced H9c2 cardiomyocyte apoptosis as revealed by caspase-3 assay, Hoechst 33258 staining, flow cytometric analysis and JC-1 staining. Molecular docking analysis showed that, pterostilbene, a natural dimethyl ether derivative of resveratrol, binds to the enzymatic active pocket of sirt1. Importantly, application of pterostilbene at low concentrations of 0.1-3.0 μM rescued H9c2 cells from apoptosis, an effect comparable with resveratrol at 20 μM. Mechanistically, pterostilbene exerted its cardioprotective effects via 1) stimulation of sirt1 activity, since pretreatment of H9c2 cells with splitomicin, an antagonist of sirt1, removed the effects of pterostilbene, and 2) enhancement of sirt1 expression. Therefore, the present study demonstrates that activation of sitr1 during ischemia-reperfusion is cardioprotective and that the natural compound-pterostilbene-could be used therapeutically to alleviate ischemia-reperfusion injury.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China; Department of Pharmacy, Taoyuan Hospital, Taoyuan, Hunan 415700, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China. Electronic address: huchangping@yahoo.com.
authors.forename: Chang-Ping
authors.initials: CP
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China. Electronic address: zzhang@csu.edu.cn.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020134:Catalytic Domain; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D062105:Molecular Docking Simulation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy; D056564:Sirtuin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D013267:Stilbenes; C107773:pterostilbene; D056564:Sirtuin 1; D010100:Oxygen
keywords: Cardiomyocyte apoptosis; Ischemia-reperfusion injury; Pterostilbene; Sirt1