title: Low-dose radiation affects cardiac physiology: gene networks and molecular signaling in cardiomyocytes.
abstract: There are 160,000 cancer patients worldwide treated with particle radiotherapy (RT). With the advent of proton, and high (H) charge (Z) and energy (E) HZE ionizing particle RT, the cardiovascular diseases risk estimates are uncertain. In addition, future deep space exploratory-type missions will expose humans to unknown but low doses of particle irradiation (IR). We examined molecular responses using transcriptome profiling in left ventricular murine cardiomyocytes isolated from mice that were exposed to 90 cGy, 1 GeV proton ((1)H) and 15 cGy, 1 GeV/nucleon iron ((56)Fe) over 28 days after exposure. Unsupervised clustering analysis of gene expression segregated samples according to the IR response and time after exposure, with (56)Fe-IR showing the greatest level of gene modulation. (1)H-IR showed little differential transcript modulation. Network analysis categorized the major differentially expressed genes into cell cycle, oxidative responses, and transcriptional regulation functional groups. Transcriptional networks identified key nodes regulating expression. Validation of the signal transduction network by protein analysis and gel shift assay showed that particle IR clearly regulates a long-lived signaling mechanism for ERK1/2, p38 MAPK signaling and identified NFATc4, GATA4, STAT3, and NF-κB as regulators of the response at specific time points. These data suggest that the molecular responses and gene expression to (56)Fe-IR in cardiomyocytes are unique and long-lasting. Our study may have significant implications for the efforts of National Aeronautics and Space Administration to develop heart disease risk estimates for astronauts and for patients receiving conventional and particle RT via identification of specific HZE-IR molecular markers.
authors.affiliation: University of California, Davis School of Medicine, Radiation Oncology, Sacramento, California; Lawrence Livermore National Laboratory, Livermore, California;
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Coleman
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts;
authors.forename: Sharath P
authors.initials: SP
authors.lastname: Sasi
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts;
authors.forename: Jillian
authors.initials: J
authors.lastname: Onufrak
authors.affiliation: University of Texas Health Science Center, San Antonio, Texas;
authors.forename: Mohan
authors.initials: M
authors.lastname: Natarajan
authors.affiliation: University of Texas Health Science Center, San Antonio, Texas;
authors.forename: Krishnan
authors.initials: K
authors.lastname: Manickam
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts;
authors.forename: John
authors.initials: J
authors.lastname: Schwab
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts;
authors.forename: Sujatha
authors.initials: S
authors.lastname: Muralidharan
authors.affiliation: Center for Biostatistics, Houston Methodist Research Institute, Houston, Texas;
authors.forename: Leif E
authors.initials: LE
authors.lastname: Peterson
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts; and.
authors.forename: Yuriy O
authors.initials: YO
authors.lastname: Alekseyev
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts; Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yan
authors.affiliation: Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts; and Tufts University School of Medicine, Boston, Massachusetts david.goukassian@tufts.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Goukassian
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016000:Cluster Analysis; D004789:Enzyme Activation; D005355:Fibrosis; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000528:radiation effects; D053263:Gene Regulatory Networks / Q000528:radiation effects*; D007504:Iron Radioisotopes / Q000633:toxicity*; D008297:Male; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D020411:Oligonucleotide Array Sequence Analysis; D011882:Radiotherapy, High-Energy / Q000009:adverse effects*; D060888:Real-Time Polymerase Chain Reaction; D018570:Risk Assessment; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects*; D013997:Time Factors; D014158:Transcription, Genetic / Q000528:radiation effects; D059467:Transcriptome / Q000528:radiation effects; D014916:Whole-Body Irradiation
chemical_list: D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D007504:Iron Radioisotopes; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020928:Mitogen-Activated Protein Kinases
keywords: cardiac physiology; cardiomyocyte; gene expression molecular signaling; radiation biology