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

Journal Article · · American Journal of Physiology: Heart and Circulatory Physiology
 [1];  [2];  [2];  [3];  [3];  [2];  [2];  [4];  [5];  [6];  [7]
  1. Univ. of California, Sacramento, CA (United States). Davis School of Medicine, Radiation Oncology; Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  2. GeneSys Research Institute, Boston, MA (United States). Cardiovascular Research Center
  3. Univ. of Texas at San Antonio, TX (United States). Health Science Center
  4. Houston Methodist Research Institute, Houston, TX (United States). Center for Biostatistics
  5. Boston Univ. School of Medicine, MA (United States). Dept. of Pathology and Laboratory Medicine
  6. GeneSys Research Institute, Boston, MA (United States). Cardiovascular Research Center; Tufts Univ. School of Medicine, Boston, MA (United States)
  7. GeneSys Research Institute, Boston, MA (United States). Cardiovascular Research Center; Boston Univ. School of Medicine, MA (United States). Dept. of Pathology and Laboratory Medicine; Tufts University School of Medicine, Boston, MA (United States)
+ Show Author Affiliations

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). Here, 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, with 56Fe-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 to 56Fe-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.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE National Nuclear Security Administration (NNSA); National Aeronautics and Space Administration (NASA); American Heart Association (AHA)
Grant/Contract Number:
AC52-07NA27344; NNX11AD22G; 14GRNT18860032; KP110202; AHA 10GRNT4710003; NHLBI HL106098; CA02802
OSTI ID:
1810689
Report Number(s):
LLNL-JRNL-737153; 890213
Journal Information:
American Journal of Physiology: Heart and Circulatory Physiology, Vol. 309, Issue 11; ISSN 0363-6135
Publisher:
American Physiological SocietyCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (7)

Metabolic changes in mice cardiac tissue after low-dose irradiation revealed by 1H NMR spectroscopy journal December 2019
Metabolic Pathway Genes Associated with Susceptibility Genes to Coronary Artery Disease journal January 2018
New therapeutic insights into radiation-induced myocardial fibrosis journal January 2019
Effects of acute exposure to low-dose radiation on the characteristics of human bone marrow mesenchymal stromal/stem cells journal September 2017
Radiation-Induced Cardiovascular Disease: Mechanisms and Importance of Linear Energy Transfer journal January 2018
SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy journal January 2019
NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models journal February 2020

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Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
cardiac physiology
cardiomyocyte radiation
biologygene
expression molecular signaling