Name: Raghda Ramadan
Date: September 30, 2019
Vergaderzaal 2.3 August Vermeylen
The role of connexin-mediated intercellular communication in radiation-induced atherosclerosis
Radiotherapy is an effective treatment for breast cancer and other thoracic malignancies. However, while radiotherapy successfully kills cancer cells, unavoidable radiation exposure to the heart and large arteries occurs during treatment, resulting in radiation-induced heart disease, especially atherosclerosis. Atherosclerosis is initiated by damage to endothelial cells that line the blood vessels. 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 intercellular communication between the endothelial cells and surrounding cells.
The aim of this PhD was to investigate the role of Cxs and their channels in radiation-induced atherosclerosis, for the aim of better risk assessment and therefore better radiation protection after thoracic radiotherapy.
We demonstrate that radiation exposure increases pro-atherogenic Cx43 levels and decreases atheroprotective Cx40 levels, potentially contributing to atherosclerosis development. In addition, radiation exposure enhances intercellular communication between endothelial cells by increasing gap junctional communication and inducing Cx43 hemichannel opening. Together, these effects promote the spread of radiation-damaging signalling thereby exacerbating endothelial cell damage and initiating atherosclerosis development.
Moreover, we show that inhibiting Cx43 hemichannels without inhibiting gap junctions protects irradiated endothelial cells against oxidative stress, cell death, chronic inflammation and premature cell senescence. These markers are known to contribute to endothelial dysfunction, an early marker for atherosclerosis. Therefore, targeting Cx43 hemichannels may help in the establishment of novel therapeutic strategies to mitigate atherosclerosis in thoracic radiotherapy treated patients.
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