title: The role of mitochondria-derived reactive oxygen species in hyperthermia-induced platelet apoptosis.
abstract: A combination of hyperthermia with radiotherapy and chemotherapy for various solid tumors has been practiced clinically. However, hyperthermic therapy has side effects, such as thrombocytopenia. Up to now, the pathogenesis of hyperthermia-induced thrombocytopenia remains unclear. Previous studies have shown that hyperthermia induces platelet apoptosis. However, the signaling pathways and molecular mechanisms involved in hyperthermia-induced platelet apoptosis have not been determined. Here we show that hyperthermia induced intracellular reactive oxygen species (ROS) production and mitochondrial ROS generation in a time-dependent manner in platelets. The mitochondria-targeted ROS scavenger Mito-TEMPO blocked intracellular ROS and mitochondrial ROS generation. By contrast, inhibitors of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nitric oxide synthase, cyclooxygenase and lipoxygenase did not. Furthermore, Mito-TEMPO inhibited hyperthermia-induced malonyldialdehyde production and cardiolipin peroxidation. We also showed that hyperthermia-triggered platelet apoptosis was inhibited by Mito-TEMPO. Furthermore, Mito-TEMPO ameliorated hyperthermia-impaired platelet aggregation and adhesion function. Lastly, hyperthermia decreased platelet manganese superoxide dismutase (MnSOD) protein levels and enzyme activity. These data indicate that mitochondrial ROS play a pivotal role in hyperthermia-induced platelet apoptosis, and decreased of MnSOD activity might, at least partially account for the enhanced ROS levels in hyperthermia-treated platelets. Therefore, determining the role of mitochondrial ROS as contributory factors in platelet apoptosis, is critical in providing a rational design of novel drugs aimed at targeting mitochondrial ROS. Such therapeutic approaches would have potential clinical utility in platelet-associated disorders involving oxidative damage.
authors.affiliation: Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China ; Department of Laboratory Medicine, Shanghai Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Cai
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chen
authors.forename: Meihong
authors.initials: M
authors.lastname: Luo
authors.forename: Lingling
authors.initials: L
authors.lastname: Hu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001792:Blood Platelets / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D002308:Cardiolipins / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced / Q000009:adverse effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D002308:Cardiolipins; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; D013481:Superoxides; D008315:Malondialdehyde; D013482:Superoxide Dismutase
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