Abstract
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.
Highlights
Radiotherapy is a common effective treatment for most tumour types, it results in an increased risk for developing radiation-related side effects such as cardiovascular diseases (CVD)[1,2,3,4,5,6,7]
telomerase immortalized human coronary artery endothelial cells (TICAE) and telomerase immortalized human dermal microvascular endothelial cells (TIME) cells were exposed to different single doses of X-rays (0.1, 0.5 and 5 Gy) and assessed for changes in connexin proteins (Cxs) gene expression at different time points (6 h, 24 h, 48 h, 72 h, 7 d and 14 d p.i.)
TICAE and TIME cells were exposed to different single doses of X-rays (0.1, 0.5 and 5 Gy) and assessed for changes in Cx protein levels at different time points (6 h, 24 h, 48 h, 72 h, 7 d and 14 d p.i.)
Summary
Radiotherapy is a common effective treatment for most tumour types, it results in an increased risk for developing radiation-related side effects such as cardiovascular diseases (CVD)[1,2,3,4,5,6,7]. Cx43 typically has a low expression in the healthy endothelium, reported to increase the formation of atherosclerotic lesions in vivo[26,27], and becomes clearly detectable at specific regions of advanced atherosclerotic plaques[21,22,23]. Cx40 may act in a similar manner: endothelial-specific deletion of Cx40 results in proatherogenic by increasing CD73-dependent leukocyte adhesion to the endothelium[31] and decreased endothelial NO signaling[29]. Cxs have been reported to be sensitive to IR and to be involved in atherosclerosis pathogenesis, their role in radiation-induced endothelial cell responses were never investigated before. For the first time, that single and fractionated X-ray irradiation modulate coronary artery and microvascular endothelial Cx gene expression, protein levels and channel function that may possibly act in a proatherogenic manner
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