Thrombomodulin Contributes to Gamma Tocotrienol-Mediated Lethality Protection and Hematopoietic Cell Recovery in Irradiated Mice
Year: 2015
Type: article
Abstract: Systemic administration of recombinant thrombomodulin (TM) confers radiation protection partly by accelerating hematopoietic recovery. The uniquely potent radioprotector gamma tocotrienol (GT3), in addition to being a strong antioxidant, inhibits the enzyme hydroxy-methyl-glutaryl-coenzyme A reductase (HMGCR) and thereby likely modulates the expression of TM. We hypothesized that the mechanism underlying the exceptional radioprotective properties of GT3 partly depends on the presence of endothelial TM. In vitro studies confirmed that ionizing radiation suppresses endothelial TM (about 40% at 4 hr after 5 Gy γ-irradiation) and that GT3 induces TM expression (about 2 fold at the mRNA level after 5 μM GT3 treatment for 4 hr). In vivo survival studies showed that GT3 was significantly more effective as a radioprotector in TM wild type (TM+/+) mice than in mice with low TM function (TMPro/-). After exposure to 9 Gy TBI, GT3 pre-treatment conferred 85% survival in TM+/+ mice compared to only 50% in TMPro/-. Thus, GT3-mediated radiation lethality protection is partly dependent on endothelial TM. Significant post-TBI recovery of hematopoietic cells, particularly leukocytes, was observed in TM+/+ mice (p = 0.003), but not in TMPro/- mice, despite the fact that GT3 induced higher levels of granulocyte colony stimulating factor (G-CSF) in TMPro/- mice (p = 0.0001). These data demonstrate a critical, G-CSF-independent, role for endothelial TM in GT3-mediated lethality protection and hematopoietic recovery after exposure to TBI and may point to new strategies to enhance the efficacy of current medical countermeasures in radiological/nuclear emergencies.
Source: PLoS ONE
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: National Aeronautics and Space Administration, Arkansas Space Grant Consortium, Edward P. Evans Foundation, National Space Biomedical Research Institute, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Awards: G168100118, Cancer Therapy-induced Long-term Bone Marrow Injury, G3168136288, Radiation-Induced Heart Disease: Mechanisms and Interventions, Molecular Pathogenesis of Radiation Enteropathy, Centers for Medical Countermeasures Against Radiation, G5665650313, G6104394639, G690245692, NATIONAL SPACE BIOMEDICAL RESEARCH INSTITUTE, ARKANSAS NASA EPSCOR PLANS TO: CONTINUE TO FUND THE NASA EPSCOR PROGRAM OFFICE TO ENSURE CONTINUED MOMENTUM AND GOOD PROGRESS IN NASA RELEVANT AEROS, G816501378, Protein C pathway function in hematopoiesis, G8392571047, G9000037057, G9000289873
OpenAlex ID: W1987569645