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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-?B 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.

SUBMITTER: Coleman MA

PROVIDER: S-EPMC4698384 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Coleman Matthew A MA Sasi Sharath P SP Onufrak Jillian J Natarajan Mohan M Manickam Krishnan K Schwab John J Muralidharan Sujatha S Peterson Leif E LE Alekseyev Yuriy O YO Yan Xinhua X Goukassian David A DA

American journal of physiology. Heart and circulatory physiology 20150925 11

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 e ...[more]

PMID: 26408534

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Project description:BACKGROUND:Myocardial fibrosis leads to impaired cardiac function and events. Extracellular volume fraction (ECV) assessed with an iodinated contrast agent and measured by cardiac CT may be a useful noninvasive marker of fibrosis. OBJECTIVE:The purpose of this study was to develop and evaluate a 3-dimensional (3D) ECV calculation toolkit (ECVTK) for ECV determination by cardiac CT. METHODS:Twenty-four subjects (10 systolic heart failure, age, 60 ± 17 years; 5 diastolic failure, age 56 ± 20 years; 9 matched healthy subjects, age 59 ± 7 years) were evaluated. Cardiac CT examinations were done on a 320-multidetector CT scanner before and after 130 mL of iopamidol (Isovue-370; Bracco Diagnostics, Plainsboro, NJ, USA) was administered. A calcium score type sequence was performed before and 7 minutes after contrast with single gantry rotation during 1 breath hold and single cardiac phase acquisition. ECV was calculated as (?HUmyocardium/?HUblood) × (1 - Hct) where Hct is the hematocrit, and ?HU is the change in Hounsfield unit attenuation = HUafter iodine - HUbefore iodine. Cardiac magnetic resonance imaging was performed to assess myocardial structure and function. RESULTS:Mean 3D ECV values were significantly higher in the subjects with systolic heart failure than in healthy subjects and subjects with diastolic heart failure (mean, 41% ± 6%, 33% ± 2%, and 35% ± 5%, respectively; P = 0.02). Interobserver and intraobserver agreements were excellent for myocardial, blood pool, and ECV (intraclass correlation coefficient, >0.90 for all). Higher 3D ECV by cardiac CT was associated with reduced systolic circumferential strain, greater end-diastolic and -systolic volumes, and lower ejection fraction (r = 0.70, r = 0.60, r = 0.73, and r = -0.68, respectively; all P < 0.001). CONCLUSION:3D ECV by cardiac CT can be performed with ECVTK. We demonstrated increased ECV in subjects with systolic heart failure compared with healthy subjects. Cardiac CT results also showed good correlation with important functional heart biomarkers, suggesting the potential for myocardial tissue characterization with the use of 3D ECV by cardiac CT. This trial is registered at www.ClinicalTrials.gov as NCT01160471.

Dataset Information

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

Publications

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

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