The Role of Connexin Proteins and Their Channels in Radiation-Induced
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Cellular and Molecular Life Sciences (2021) 78:3087–3103 https://doi.org/10.1007/s00018-020-03716-3 Cellular andMolecular Life Sciences REVIEW The role of connexin proteins and their channels in radiation‑induced atherosclerosis Raghda Ramadan1,2 · Sarah Baatout1,3 · An Aerts1 · Luc Leybaert2 Received: 16 July 2020 / Revised: 29 October 2020 / Accepted: 17 November 2020 / Published online: 3 January 2021 © The Author(s) 2021 Abstract Radiotherapy is an efective 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 infam- mation, 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 defned. A better understanding of the underlying biological pathways involved in secondary cardiovascular toxicity after radiotherapy would facilitate the development of efective strategies that prevent or mitigate these adverse efects. Here, we review the possible roles of intercellular Cx driven signaling and communication in radiation-induced atherosclerosis. Keywords Ionizing radiation · Atherosclerosis · Intercellular communication · Bystander efect · Connexin · Gap junction · Hemichannels Abbreviations IR Ionizing radiation ATP Adenosine triphosphate IP3 Inositol triphosphate Cx Connexion IL Interleukin CVD Cardiovascular diseases JNK C-jun N-terminal kinase CL Cytoplasmic loop kDa Kilo-Dalton CT C-terminal tail LDL Low-density lipoprotein COX-2 Cyclooxygenase-2 MAPK Mitogen-activated protein kinase DNA Deoxyribonucleic acid MCP-1 Monocyte chemotactic protein-1 DSB Double-strand breaks NF-κB Nuclear factor kappa-light-chain-enhancer of eNOS Endothelial nitric oxide synthase activated B cells EL Extracellular loop NO Nitric oxide Gy Gray NT NH2 termini RIBE Radiation-induced bystander efect * Luc Leybaert ROS Reactive oxygen species [email protected] RNS Reactive nitrogen species SSB Single-strand break 1 Radiobiology Unit, Belgian Nuclear Research Centre (SCK TGF Transforming growth factor CEN), Mol, Belgium TNF Tumor necrosis factor 2 Department of Basic and Applied Medical Sciences, TM Transmembrane domain Physiology group, Ghent University, Ghent, Belgium VCAM-1 Vascular cell adhesion molecule 1 3 Department of Molecular Biotechnology, Ghent University, Ghent, Belgium Vol.:(0123456789)1 3 3088 R. Ramadan et al. Introduction Intercellular communication in atherosclerosis development Cardiovascular disease (CVD) is the leading cause of mor- and the response to ionizing radiation bidity and mortality worldwide, with 31% of all global exposure deaths in 2016, according to the World Health Organization (WHO). The most common causes of CVD morbidity and Radiation‑induced bystander efect (RIBE) mortality are myocardial infarction, stroke, coronary artery disease, and congestive heart failure [1]. Atherosclerosis is Biological responses in non-irradiated cells are defned considered the major underlying cause of CVD development as non-targeted efects [35], which may include genomic [2]. The progression of atherosclerosis and the risk of CVD instability, bystander efects, and abscopal efects [35–37]. are infuenced by the presence of a combination of risk fac- Radiation-induced genomic instability can be observed as tors, such as dietary factors, tobacco use, physical inactiv- a delayed and stochastic appearance of de novo gene muta- ity, hypertension, age, gender, hyperlipidemia, and genetic tions, chromosomal aberrations, and reproductive cell death predisposition [3]. Growing evidence indicates that exposure in the progeny of irradiated cells [38]. Bystander efect per- to ionizing radiation (IR) is also associated with an increased tains to cells adjacent to irradiated cells, while the abscopal risk of CVD [4–12]. efect may reach further tissues outside of the irradiated vol- The medical use of IR plays a key role in cancer treatment ume, and it relies more on clinical observations in patients with about 50% of cancer patients receiving radiotherapy for receiving radiotherapy [35, 39]. curative and/or supportive therapy during the course of their treatment [13]. Incidental IR exposure to the heart and large RIBE: experimental data arteries occurs during radiotherapy for thoracic malignan- cies such as breast cancer, head and neck cancer, Hodgkin’s In vitro studies Traditionally, it was accepted that expo- lymphoma, and esophageal cancer [14]. Large-scale epide- sure to IR only afected directly irradiated cells. However, miological studies have established a link between high and in 1992, Nagasawa et al. reported that irradiating 1% of medium doses of IR exposure (> 0.5 Gy) and the risk for Chinese hamster ovary cells with α-particles led to genetic CVD [5, 9, 11, 15–17]. In addition, meta-analyses of epide- damage in more than 30% of cells [40]. This observation miological studies, and other experimental studies suggest was later confrmed by others in human fbroblast cells [41]. that even low radiation doses (< 0.5 Gy) can generate car- This means that non-irradiated cells exhibit efects as a result diovascular morbidity [7, 9, 18–23]. of signals received from adjacent irradiated cells, a process Radiation treatment is known to cause cellular efects known as radiation-induced bystander efect (RIBE) [34, such as oxidative stress, DNA damage, cellular Ca2+ over- 42]. Since then, RIBE has been observed in several in vitro load, apoptosis, premature cell senescence and promotes studies for diferent biological endpoints such as cell death, infammation which may induce vascular endothelium dam- apoptosis, senescence, DNA damage, gene mutations, chro- age, an early marker for atherosclerosis [24–30] (reviewed in mosomal aberrations, genomic instability, cell diferentia- [31, 32]). Cellular and molecular changes induced by radia- tion, cell cycle distribution, and gene expression (reviewed tion exposure occur not only in directly irradiated cells, but in [43, 44], and [45]). Bystander efects have mainly been also in neighboring non-irradiated cells, a process known studied in vitro using various techniques (medium trans- as the ’radiation-induced bystander efect’ (RIBE) [33, 34]. fer, co-culture method and microbeam irradiation which Transmembrane connexin (Cx) proteins are critical modula- provided clear evidence of RIBE) [43, 46, 47], distinct cell tors of this process by forming gap junction channels that types (normal and cancerous cells) [41, 48, 49], and difer- provide intercellular communication routes between neigh- ent culture systems (two and three-dimensional models) boring cells, and hemichannels, that mediate paracrine com- [49, 50]. RIBE has been reported to be induced both by munication pathway. While understanding of the molecular high-LET irradiation [47, 51–53], as well as low-LET irra- mechanisms of IR-induced atherosclerosis has increased, diation after high doses (> 2 Gy) [54–56], medium and low the role of intercellular communication, particularly the role doses of exposure (> 2 Gy) [57–59], utilizing a variety of of endothelial Cxs and their channels, in the development dose rates [60]. These studies showed that RIBE depends on of radiation-induced atherosclerosis is still poorly defned. radiation quality, radiation dose, and dose rate used. RIBE Here, we review the role of intercellular communication in was also reported in response to fractionated irradiation radiation-induced atherosclerosis, with the focus on radia- exposure commonly used in radiotherapy, which appears to tion-induced bystander response and a possible role of Cxs be dependent on cell type, dose/dose rate, and the interval in radiation-induced atherosclerosis. between fractions [61, 62]. 1 3 3089 The role of connexin proteins and their channels in radiation-induced atherosclerosis High- and low-LET radiation experimental in vitro evi- reported a decrease in the bone marrow cellularity of chil- dence overall indicates that the classic bystander efect is dren that received X-irradiation to their spleen for chronic detrimental for the cells [38, 51, 63–65]. However, non- granulocytic leukemia treatment [83]. Since then, several classic bystander efects have also been described, reporting studies reported abscopal efects in cases where radio- increased survival of bystander cells after high dose irradia- therapy was combined with immune checkpoint inhibitors tion [66]. Moreover, the so-called radiation-induced adap- or immunotherapeutic agents that enhance the immune tive response, which is the acquisition of radiation resistance response in general [84–86]. Abscopal efects may in prin- induced by priming the cells