The role of connexin proteins and their channels in radiation-induced atherosclerosis

Abstract

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.

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

“…Radiation-induced vascular injury is commonly observed in cancer patients after radiation therapy ( Murphy et al, 2012 ; Venkatesulu et al, 2019 ; Ramadan et al, 2021 ). The major drivers of radiation-induced vascular injury are oxidative stress, DNA damage, and inflammation ( Lafargue et al, 2017 ; Baselet et al, 2019 ).…”

EANM position paper on the role of radiobiology in nuclear medicine

“…Furthermore, ionizing radiation can harm supramolecular structures like cellular membranes, mitochondria, the endoplasmic reticulum, the Golgi apparatus, the lysosomal system, and the cytoskeleton [80]. Finally, also aspects beyond cellular boundaries are increasingly being considered in radiobiology, like the tumor microenvironment, intercellular communication, immune responses, and the abscopal effect [81,82].…”

New Insights on the Role of Connexins and Gap Junctions Channels in Adipose Tissue and Obesity

“…Additionally, GJs are the basis of electrical coupling in excitable cells such as neurons and heart cells, mediating action potential propagation [35]. Alterations in the regulation of their expression and their cellular distribution are related to different diseases [36], for instance tumors [37], epilepsy [38], atherosclerosis [39], and heart diseases [40]. Gap junc- Twenty-one different types of Cxs have been described in the human and mouse genome, in addition to an increasing number of orthologs in other vertebrates [32].…”

“…Additionally, GJs are the basis of electrical coupling in excitable cells such as neurons and heart cells, mediating action potential propagation [35]. Alterations in the regulation of their expression and their cellular distribution are related to different diseases [36], for instance tumors [37], epilepsy [38], atherosclerosis [39], and heart diseases [40]. Gap junctions allow the coordinated transport of small molecules, such as ions, amino acids, nucleotides, second messengers (Ca 2+ , cAMP, cGMP, IP3), and various metabolites such as ADP, glucose, lactate, and glutamate [41].…”

“…Different studies have shown the intimate relationship between obesity and atrial fibrillation (AF) [91,92]. Atrial fibrillation is the most common type of heart arrhythmia, where the central feature is very rapid and uncoordinated atrial activity [39]. A key feature of AF is atrial enlargement and remodeling in the expression, function, and location of cardiac Cxs [93][94][95].…”