Figure 3.

After sublethal irradiation, multiple events in the nucleus and cytoplasm contribute to the inflammatory state responsible for RICVD. In the cytoplasm, (1) sublethal irradiation of an off-target cell leads to (2) ROS formation and (3) ROS-induced-ROS release from the mitochondria. (4) ROS lead to ligand-independent activation of RTK which leads to expression of many pathways that (5) induce NF-κB. In the nucleus, (1) sublethal ionizing radiation leads to (6) ROS formation and single-stranded DNA breaks. (7) In response to DNA damage, ATM and ATM and AT and Rad3-related kinase are activated. (8) They induce p53 activation leading to cell cycle arrest and DNA repair as well as (9) inducing NF-κB. (10) NF-κB activation from both pathways induces factors that lead to antiapoptotic, radiation resistance, and inflammatory signaling. The presented mechanism is generally expected to occur in all sublethally irradiated cell types, but the pathogenesis of RICVD is first seen in the endothelial cells. Abbreviations: RICVD, radiation-induced cardiovascular disease; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; NF-κB, nuclear factor kappa B; ATM, ataxia-telangiectasia mutated kinase.