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

Matthew A. Coleman, Sharath P. Sasi, Jillian Onufrak, Mohan Natarajan, Krishnan Manickam, John Schwab, Sujatha Muralidharan, Leif E. Peterson, Yuriy O. Alekseyev, Xinhua Yan, David A. Goukassian

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Pages (from-to)H1947-H1963
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number11
DOIs
StatePublished - 2015

Fingerprint

Gene Regulatory Networks
Cardiac Myocytes
Radiotherapy
Radiation
Protons
Cosmic Radiation
United States National Aeronautics and Space Administration
Astronauts
Gene Expression
cdc Genes
Gene Expression Profiling
Electrophoretic Mobility Shift Assay
p38 Mitogen-Activated Protein Kinases
Reaction Time
Cluster Analysis
Heart Diseases
Signal Transduction
Cardiovascular Diseases
Iron
Genes

Keywords

  • Cardiac physiology
  • Cardiomyocyte
  • Gene expression molecular signaling
  • Radiation biology

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Low-dose radiation affects cardiac physiology : Gene networks and molecular signaling in cardiomyocytes. / Coleman, Matthew A.; Sasi, Sharath P.; Onufrak, Jillian; Natarajan, Mohan; Manickam, Krishnan; Schwab, John; Muralidharan, Sujatha; Peterson, Leif E.; Alekseyev, Yuriy O.; Yan, Xinhua; Goukassian, David A.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 309, No. 11, 2015, p. H1947-H1963.

Research output: Contribution to journalArticle

Coleman, MA, Sasi, SP, Onufrak, J, Natarajan, M, Manickam, K, Schwab, J, Muralidharan, S, Peterson, LE, Alekseyev, YO, Yan, X & Goukassian, DA 2015, 'Low-dose radiation affects cardiac physiology: Gene networks and molecular signaling in cardiomyocytes', American Journal of Physiology - Heart and Circulatory Physiology, vol. 309, no. 11, pp. H1947-H1963. https://doi.org/10.1152/ajpheart.00050.2015
Coleman, Matthew A. ; Sasi, Sharath P. ; Onufrak, Jillian ; Natarajan, Mohan ; Manickam, Krishnan ; Schwab, John ; Muralidharan, Sujatha ; Peterson, Leif E. ; Alekseyev, Yuriy O. ; Yan, Xinhua ; Goukassian, David A. / Low-dose radiation affects cardiac physiology : Gene networks and molecular signaling in cardiomyocytes. In: American Journal of Physiology - Heart and Circulatory Physiology. 2015 ; Vol. 309, No. 11. pp. H1947-H1963.
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