Low-dose radiation affects cardiac physiology: gene networks and molecular signaling in cardiomyocytes

American Journal of Physiology - Heart and Circulatory Physiology - Tập 309 Số 11 - Trang H1947-H1963 - 2015
Matthew A. Coleman1,2, Sharath P. Sasi3, Jillian Onufrak3, Mohan Natarajan4, Manickam Krishnan4, John H. Schwab3, Sujatha Muralidharan3, L. E. Peterson5, Yuriy O. Alekseyev6, Xinhua Yan3,7, David A. Goukassian3,6,7
1Lawrence Livermore National Laboratory, Livermore, California
2University of California, Davis School of Medicine, Radiation Oncology, Sacramento, California;
3Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts;
4University of Texas Health Science Center, San Antonio, Texas
5Center for Biostatistics, Houston Methodist Research Institute, Houston, Texas;
6Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts; and
7Tufts University School of Medicine, Boston, Massachusetts

Tóm tắt

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 (1H) and 15 cGy, 1 GeV/nucleon iron (56Fe) over 28 days after exposure. Unsupervised clustering analysis of gene expression segregated samples according to the IR response and time after exposure, with56Fe-IR showing the greatest level of gene modulation.1H-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 to56Fe-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.

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