title: A dose-dependent perturbation in cardiac energy metabolism is linked to radiation-induced ischemic heart disease in Mayak nuclear workers.
abstract: Epidemiological studies show a significant increase in ischemic heart disease (IHD) incidence associated with total external gamma-ray dose among Mayak plutonium enrichment plant workers. Our previous studies using mouse models suggest that persistent alteration of heart metabolism due to the inhibition of peroxisome proliferator-activated receptor (PPAR) alpha accompanies cardiac damage after high doses of ionising radiation. The aim of the present study was to elucidate the mechanism of radiation-induced IHD in humans. The cardiac proteome response to irradiation was analysed in Mayak workers who were exposed only to external doses of gamma rays. All participants were diagnosed during their lifetime with IHD that also was the cause of death. Label-free quantitative proteomics analysis was performed on tissue samples from the cardiac left ventricles of individuals stratified into four radiation dose groups (0 Gy, < 100 mGy, 100-500 mGy, and > 500 mGy). The groups could be separated using principal component analysis based on all proteomics features. Proteome profiling showed a dose-dependent increase in the number of downregulated mitochondrial and structural proteins. Both proteomics and immunoblotting showed decreased expression of several oxidative stress responsive proteins in the irradiated hearts. The phosphorylation of transcription factor PPAR alpha was increased in a dose-dependent manner, which is indicative of a reduction in transcriptional activity with increased radiation dose. These data suggest that chronic external radiation enhances the risk for IHD by inhibiting PPAR alpha and altering the expression of mitochondrial, structural, and antioxidant components of the heart.
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Institute of Radiation Biology, Neuherberg, Germany.
authors.forename: Omid
authors.initials: O
authors.lastname: Azimzadeh
authors.affiliation: Southern Urals Biophysics Institute, Russian Federation, Ozyorsk, Russia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Azizova
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Research Unit Protein Science, Munich, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Merl-Pham
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Institute of Radiation Biology, Neuherberg, Germany.
authors.forename: Vikram
authors.initials: V
authors.lastname: Subramanian
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Institute of Radiation Biology, Neuherberg, Germany.
authors.forename: Mayur V
authors.initials: MV
authors.lastname: Bakshi
authors.affiliation: Southern Urals Biophysics Institute, Russian Federation, Ozyorsk, Russia.
authors.forename: Maria
authors.initials: M
authors.lastname: Moseeva
authors.affiliation: Southern Urals Biophysics Institute, Russian Federation, Ozyorsk, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Zubkova
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Research Unit Protein Science, Munich, Germany.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Institute of Radiation Biology, Neuherberg, Germany.
authors.forename: Nataša
authors.initials: N
authors.lastname: Anastasov
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Institute of Radiation Biology, Neuherberg, Germany.|Chair of Radiation Biology, Technical University of Munich, Munich, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Atkinson
authors.affiliation: Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Institute of Radiation Biology, Neuherberg, Germany.
authors.forename: Soile
authors.initials: S
authors.lastname: Tapio
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D016022:Case-Control Studies; D002423:Cause of Death; D004307:Dose-Response Relationship, Radiation; D004734:Energy Metabolism / Q000528:radiation effects*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism / Q000528:radiation effects; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000528:radiation effects*; D016273:Occupational Exposure / Q000009:adverse effects*; D016272:Occupational Health; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism; D010766:Phosphorylation; D011005:Plutonium / Q000009:adverse effects*; D025341:Principal Component Analysis; D060066:Protein Interaction Maps; D040901:Proteomics / Q000379:methods; D011832:Radiation Injuries / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D018570:Risk Assessment; D012307:Risk Factors; D012426:Russia
chemical_list: D000975:Antioxidants; D035683:MicroRNAs; D047493:PPAR alpha; D011005:Plutonium
keywords: PPAR alpha; heart disease; ionising radiation; mitochondrial dysfunction; proteomics