The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation

• Published in: PloS one 2013-08, Vol.8 (8), p.e70024
• Main Authors: Yentrapalli, Ramesh, Azimzadeh, Omid, Sriharshan, Arundhathi, Malinowsky, Katharina, Merl, Juliane, Wojcik, Andrzej, Harms-Ringdahl, Mats, Atkinson, Michael J, Becker, Karl-Friedrich, Haghdoost, Siamak, Tapio, Soile
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Aging; Aging (Biology); AKT protein; Atherosclerosis; Biology; Cardiovascular disease; Cardiovascular diseases; Cell Proliferation - radiation effects; Cellular Senescence - radiation effects; Chronic exposure; Coronary vessels; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cytoskeleton; Deactivation; Dose-Response Relationship, Radiation; Endothelial cells; Endothelium; Environmental health; Etiology; Exposure; Galactosidase; Gamma rays; GTP-binding protein; Health aspects; Heart; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - radiation effects; Humans; Inactivation; Ionizing radiation; Medical imaging; Mortality; Phosphatidylinositol 3-Kinases - metabolism; Physics; Protein arrays; Proteins; Proteomics; Proto-Oncogene Proteins c-akt - metabolism; Radiation; Radiation dosage; Radiation effects; Risk factors; Senescence; Signal transduction; Signal Transduction - radiation effects; Signaling; Time Factors; TOR protein; TOR Serine-Threonine Kinases - metabolism; Umbilical vein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0070024

The etiology of radiation-induced cardiovascular disease (CVD) after chronic exposure to low doses of ionizing radiation is only marginally understood. We have previously shown that a chronic low-dose rate exposure (4.1 mGy/h) causes human umbilical vein endothelial cells (HUVECs) to prematurely senesce. We now show that a dose rate of 2.4 mGy/h is also able to trigger premature senescence in HUVECs, primarily indicated by a loss of growth potential and the appearance of the senescence-associated markers ß-galactosidase (SA-ß-gal) and p21. In contrast, a lower dose rate of 1.4 mGy/h was not sufficient to inhibit cellular growth or increase SA-ß-gal-staining despite an increased expression of p21. We used reverse phase protein arrays and triplex Isotope Coded Protein Labeling with LC-ESI-MS/MS to study the proteomic changes associated with chronic radiation-induced senescence. Both technologies identified inactivation of the PI3K/Akt/mTOR pathway accompanying premature senescence. In addition, expression of proteins involved in cytoskeletal structure and EIF2 signaling was reduced. Age-related diseases such as CVD have been previously associated with increased endothelial cell senescence. We postulate that a similar endothelial aging may contribute to the increased rate of CVD seen in populations chronically exposed to low-dose-rate radiation.