A dose-dependent perturbation in cardiac energy metabolism is linked to radiation-induced ischemic heart disease in Mayak nuclear workers

• Published in: Oncotarget Vol. 8; no. 6; pp. 9067 - 9078
• Main Authors: Azimzadeh, Omid, Azizova, Tamara, Merl-Pham, Juliane, Subramanian, Vikram, Bakshi, Mayur V, Moseeva, Maria, Zubkova, Olga, Hauck, Stefanie M, Anastasov, Nataša, Atkinson, Michael J, Tapio, Soile
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 07.02.2017
• Subjects: Antioxidants - metabolism; Case-Control Studies; Cause of Death; Dose-Response Relationship, Radiation; Energy Metabolism - radiation effects; Humans; Male; MicroRNAs - genetics; MicroRNAs - metabolism; Mitochondria, Heart - metabolism; Mitochondria, Heart - radiation effects; Myocardial Ischemia - diagnosis; Myocardial Ischemia - etiology; Myocardial Ischemia - metabolism; Myocardial Ischemia - mortality; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - radiation effects; Occupational Exposure - adverse effects; Occupational Health; Oxidative Stress; Phosphorylation; Plutonium - adverse effects; PPAR alpha - metabolism; Principal Component Analysis; Protein Interaction Maps; Proteomics - methods; Radiation Injuries - diagnosis; Radiation Injuries - etiology; Radiation Injuries - metabolism; Radiation Injuries - mortality; Research Paper; Risk Assessment; Risk Factors; Russia; PPAR alpha; ionising radiation; mitochondrial dysfunction; proteomics; heart disease
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.10424

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.