pr400071g_si_001.pdf (8.49 MB)
PPAR Alpha: A Novel Radiation Target in Locally Exposed Mus musculus Heart Revealed by Quantitative Proteomics
journal contribution
posted on 2013-06-07, 00:00 authored by Omid Azimzadeh, Wolfgang Sievert, Hakan Sarioglu, Ramesh Yentrapalli, Zarko Barjaktarovic, Arundhathi Sriharshan, Marius Ueffing, Dirk Janik, Michaela Aichler, Michael
J. Atkinson, Gabriele Multhoff, Soile TapioRadiation
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.