Although radiotherapy is commonly used to treat cancer, its beneficial outcome is frequently hampered by the radiation resistance of tumor cells and adverse reactions in normal tissues. Mechanisms of cell-to-cell communication and how intercellular signals are translated into cellular responses, have become topics of intense investigation, particularly within the field of radiobiology. A substantial amount of evidence is available demonstrating that both gap junctional and paracrine communication pathways can propagate radiation-induced biological effects at the intercellular level, commonly referred to as radiation-induced bystander effects (RIBE). Multiple molecular signaling mechanisms involving oxidative stress, kinases, inflammatory molecules, and Ca are postulated to contribute to RIBE. Ca is a highly versatile and ubiquitous second messenger that regulates diverse cellular processes via the interaction with various signaling cascades. It furthermore provides a fast system for the dissemination of information at the intercellular level. Channels formed by transmembrane connexin (Cx) proteins, i.e. hemichannels and gap junction channels, can mediate the cell-to-cell propagation of increases in intracellular Ca by ministering paracrine and direct cell-cell communication, respectively. We here review current knowledge on radiation-induced signaling mechanisms in irradiated and bystander cells, particularly focusing on the contribution of oxidative stress, Ca and Cx channels. By illustrating the tight interplay between these different partners, we provide a conceptual framework for intercellular Ca signaling as a key player in modulating the RIBE and the overall response to radiation.

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Background: Emerging evidence indicates an excess risk of late occurring cardiovascular diseases, especially atherosclerosis, after thoracic cancer radiotherapy. Ionizing radiation (IR) induces cellular effects which may induce endothelial cell dysfunction, an early marker for atherosclerosis. In addition, intercellular communication through channels composed of transmembrane connexin proteins (Cxs), i.e. Gap junctions (direct cell-cell coupling) and hemichannels (paracrine release/uptake pathway) can modulate radiation-induced responses and therefore the atherosclerotic process. However, the role of endothelial hemichannel in IR-induced atherosclerosis has never been described before. Materials and Methods: Telomerase-immortalized human Coronary Artery/ Microvascular Endothelial cells (TICAE/TIME) were exposed to X-rays (0.1 and 5 Gy). Production of reactive oxygen species (ROS), DNA damage, cell death, inflammatory responses, and senescence were assessed with or without applying a Cx43 hemichannel blocker (TAT-Gap19). Results: We report here that IR induces an increase in oxidative stress, cell death, inflammatory responses (IL-8, IL-1β, VCAM-1, MCP-1, and Endothelin-1) and premature cellular senescence in TICAE and TIME cells. These effects are significantly reduced in the presence of the Cx43 hemichannel-targeting peptide TAT-Gap19. Conclusion: Our findings suggest that endothelial Cx43 hemichannels contribute to various IR-induced processes, such as ROS, cell death, inflammation, and senescence, resulting in an increase in endothelial cell damage, which could be protected by blocking these hemichannels. Thus, targeting Cx43 hemichannels may potentially exert radioprotective effects.

Radiotherapy is an effective treatment for most tumor types. However, emerging evidence indicates an increased risk for atherosclerosis after ionizing radiation exposure, initiated by endothelial cell dysfunction. Interestingly, endothelial cells express connexin (Cx) proteins that are reported to exert proatherogenic as well as atheroprotective effects. Furthermore, Cxs form channels, gap junctions and hemichannels, that are involved in bystander signaling that leads to indirect radiation effects in non-exposed cells. We here aimed to investigate the consequences of endothelial cell irradiation on Cx expression and channel function. Telomerase immortalized human Coronary Artery/Microvascular Endothelial cells were exposed to single and fractionated X-rays. Several biological endpoints were investigated at different time points after exposure: Cx gene and protein expression, gap junctional dye coupling and hemichannel function. We demonstrate that single and fractionated irradiation induce upregulation of proatherogenic Cx43 and downregulation of atheroprotective Cx40 gene and protein levels in a dose-dependent manner. Single and fractionated irradiation furthermore increased gap junctional communication and induced hemichannel opening. Our findings indicate alterations in Cx expression that are typically observed in endothelial cells covering atherosclerotic plaques. The observed radiation-induced increase in Cx channel function may promote bystander signaling thereby exacerbating endothelial cell damage and atherogenesis.

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Radiotherapy is an effective treatment for breast cancer and other thoracic tumors. However, while high-energy radiotherapy treatment successfully kills cancer cells, radiation exposure of the heart and large arteries cannot always be avoided, resulting in secondary cardiovascular disease in cancer survivors. Radiation-induced changes in the cardiac vasculature may thereby lead to coronary artery atherosclerosis, which is a major cardiovascular complication nowadays in thoracic radiotherapy-treated patients. The underlying biological and molecular mechanisms of radiation-induced atherosclerosis are complex and still not fully understood, resulting in potentially improper radiation protection. Ionizing radiation (IR) exposure may damage the vascular endothelium by inducing DNA damage, oxidative stress, premature cellular senescence, cell death and inflammation, which act to promote the atherosclerotic process. Intercellular communication mediated by connexin (Cx)-based gap junctions and hemichannels may modulate IR-induced responses and thereby the atherosclerotic process. However, the role of endothelial Cxs and their channels in atherosclerotic development after IR exposure is still poorly defined. A better understanding of the underlying biological pathways involved in secondary cardiovascular toxicity after radiotherapy would facilitate the development of effective strategies that prevent or mitigate these adverse effects. Here, we review the possible roles of intercellular Cx driven signaling and communication in radiation-induced atherosclerosis.

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