The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation.
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.
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Radiation Biology, Neuherberg, Germany.
Ramesh
R
Yentrapalli
Omid
O
Azimzadeh
Arundhathi
A
Sriharshan
Katharina
K
Malinowsky
Juliane
J
Merl
Andrzej
A
Wojcik
Mats
M
Harms-Ringdahl
Michael J
MJ
Atkinson
Karl-Friedrich
KF
Becker
Siamak
S
Haghdoost
Soile
S
Tapio
D049109:Cell Proliferation / Q000528:radiation effects; D016922:Cellular Senescence / Q000528:radiation effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000528:radiation effects*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors
D050759:Cyclin-Dependent Kinase Inhibitor p21; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases