title: PPAR alpha: a novel radiation target in locally exposed Mus musculus heart revealed by quantitative proteomics.
abstract: Radiation exposure of the thorax is associated with a markedly increased risk of cardiac morbidity and mortality with a latency period of decades. Although many studies have confirmed the damaging effect of ionizing radiation on the myocardium and cardiac endothelial structure and function, the molecular mechanism behind this damage is not yet elucidated. Peroxisome proliferator-activated receptor alpha (PPAR alpha), a transcriptional regulator of lipid metabolism in heart tissue, has recently received great attention in the development of cardiovascular disease. The goal of this study was to investigate radiation-induced cardiac damage in general and the role of PPAR alpha in this process in particular. C57BL/6 mice received local heart irradiation with X-ray doses of 8 and 16 gray (Gy) at the age of 8 weeks. The mice were sacrificed 16 weeks later. Radiation-induced changes in the cardiac proteome were quantified using the Isotope Coded Protein Label (ICPL) method followed by mass spectrometry and software analysis. Significant alterations were observed in proteins involved in lipid metabolism and oxidative phosphorylation. Ionizing radiation markedly changed the phosphorylation and ubiquitination status of PPAR alpha. This was reflected as decreased expression of its target genes involved in energy metabolism and mitochondrial respiratory chain confirming the proteomics data. This study suggests that persistent alteration of cardiac metabolism due to impaired PPAR alpha activity contributes to the heart pathology after radiation.
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Radiation Biology, Neuherberg, Germany. omid.azimzadeh@helmholtz-muenchen.de
authors.forename: Omid
authors.initials: O
authors.lastname: Azimzadeh
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sievert
authors.forename: Hakan
authors.initials: H
authors.lastname: Sarioglu
authors.forename: Ramesh
authors.initials: R
authors.lastname: Yentrapalli
authors.forename: Zarko
authors.initials: Z
authors.lastname: Barjaktarovic
authors.forename: Arundhathi
authors.initials: A
authors.lastname: Sriharshan
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.forename: Dirk
authors.initials: D
authors.lastname: Janik
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Atkinson
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
authors.forename: Soile
authors.initials: S
authors.lastname: Tapio
mesh_terms: D000818:Animals; D015870:Gene Expression / Q000528:radiation effects; D006321:Heart / Q000503:physiopathology / Q000528:radiation effects*; D050356:Lipid Metabolism / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism / Q000528:radiation effects*; D010085:Oxidative Phosphorylation / Q000528:radiation effects; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D025941:Protein Interaction Mapping; D040901:Proteomics; D015398:Signal Transduction; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D014965:X-Rays
chemical_list: D047493:PPAR alpha