Role of TGF Beta and PPAR Alpha Signaling Pathways in Radiation Response of Locally Exposed Heart: Integrated Global Transcriptomics and Proteomics Analysis.
Epidemiological data from patients undergoing radiotherapy for thoracic tumors clearly show the damaging effect of ionizing radiation on cardiovascular system. The long-term impairment of heart function and structure after local high-dose irradiation is associated with systemic inflammatory response, contraction impairment, microvascular damage, and cardiac fibrosis. The goal of the present study was to investigate molecular mechanisms involved in this process. C57BL/6J mice received a single X-ray dose of 16 Gy given locally to the heart at the age of 8 weeks. Radiation-induced changes in the heart transcriptome and proteome were investigated 40 weeks after the exposure. The omics data were analyzed by bioinformatics tools and validated by immunoblotting. Integrated network analysis of transcriptomics and proteomics data elucidated the signaling pathways that were similarly affected at gene and protein level. Analysis showed induction of transforming growth factor (TGF) beta signaling but inactivation of peroxisome proliferator-activated receptor (PPAR) alpha signaling in irradiated heart. The putative mediator role of mitogen-activated protein kinase cascade linking PPAR alpha and TGF beta signaling was supported by data from immunoblotting and ELISA. This study indicates that both signaling pathways are involved in radiation-induced heart fibrosis, metabolic disordering, and impaired contractility, a pathophysiological condition that is often observed in patients that received high radiation doses in thorax.
Helmholtz Zentrum München - German Research Center for Environmental Health GmbH , Institute of Radiation Biology, 85764 Neuherberg, Germany.
Vikram
V
Subramanian
Division of Biological Stress Response, Netherlands Cancer Institute , 1006 BE Amsterdam, The Netherlands.
Ingar
I
Seemann
Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health GmbH , Research Unit Protein Science, 80939 Munich, Germany.
Juliane
J
Merl-Pham
Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health GmbH , Research Unit Protein Science, 80939 Munich, Germany.
Stefanie M
SM
Hauck
Division of Biological Stress Response, Netherlands Cancer Institute , 1006 BE Amsterdam, The Netherlands.
Fiona A
FA
Stewart
Helmholtz Zentrum München - German Research Center for Environmental Health GmbH , Institute of Radiation Biology, 85764 Neuherberg, Germany.|Chair of Radiation Biology, Technical University of Munich , 81675 Munich, Germany.
Michael J
MJ
Atkinson
Helmholtz Zentrum München - German Research Center for Environmental Health GmbH , Institute of Radiation Biology, 85764 Neuherberg, Germany.
Soile
S
Tapio
Helmholtz Zentrum München - German Research Center for Environmental Health GmbH , Institute of Radiation Biology, 85764 Neuherberg, Germany.
Omid
O
Azimzadeh
D000818:Animals; D019295:Computational Biology; D004719:Endomyocardial Fibrosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005720:Gamma Rays / Q000009:adverse effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D020543:Proteome / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D047493:PPAR alpha; D020543:Proteome; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases
PPAR alpha; TGF beta; cardiovascular disease; heart; ionizing radiation; label-free quantification; proteomics; transcriptomics