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Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

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Abstract
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-1 beta, 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.
Keywords
Pharmacology (medical), Pharmacology, DOSE IONIZING-RADIATION, INFLAMMATORY PLAQUE PHENOTYPE, CHRONIC OXIDATIVE STRESS, GAP-JUNCTION CHANNELS, DNA-DAMAGE, MIMETIC PEPTIDE, HEART-DISEASE, CARDIOVASCULAR-DISEASE, REDUCES INFLAMMATION, SECRETORY PHENOTYPE, atherosclerosis, endothelial damage, ionizing radiation, connexin43 hemichannels, TAT-Gap19

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MLA
Ramadan, Raghda, et al. “Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage.” FRONTIERS IN PHARMACOLOGY, vol. 11, 2020.
APA
Ramadan, R., Vromans, E., Anang, D. C., Goetschalckx, I., Hoorelbeke, D., Decrock, E., … Aerts, A. (2020). Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage. FRONTIERS IN PHARMACOLOGY, 11.
Chicago author-date
Ramadan, Raghda, Els Vromans, Dornatien Chuo Anang, Ines Goetschalckx, Delphine Hoorelbeke, Elke Decrock, Sarah Baatout, Luc Leybaert, and An Aerts. 2020. “Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage.” FRONTIERS IN PHARMACOLOGY 11.
Chicago author-date (all authors)
Ramadan, Raghda, Els Vromans, Dornatien Chuo Anang, Ines Goetschalckx, Delphine Hoorelbeke, Elke Decrock, Sarah Baatout, Luc Leybaert, and An Aerts. 2020. “Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage.” FRONTIERS IN PHARMACOLOGY 11.
Vancouver
1.
Ramadan R, Vromans E, Anang DC, Goetschalckx I, Hoorelbeke D, Decrock E, et al. Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage. FRONTIERS IN PHARMACOLOGY. 2020;11.
IEEE
[1]
R. Ramadan et al., “Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage,” FRONTIERS IN PHARMACOLOGY, vol. 11, 2020.
@article{8663262,
  abstract     = {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-1 beta, 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.},
  author       = {Ramadan, Raghda and Vromans, Els and Anang, Dornatien Chuo and Goetschalckx, Ines and Hoorelbeke, Delphine and Decrock, Elke and Baatout, Sarah and Leybaert, Luc and Aerts, An},
  issn         = {1663-9812},
  journal      = {FRONTIERS IN PHARMACOLOGY},
  keywords     = {Pharmacology (medical),Pharmacology,DOSE IONIZING-RADIATION,INFLAMMATORY PLAQUE PHENOTYPE,CHRONIC OXIDATIVE STRESS,GAP-JUNCTION CHANNELS,DNA-DAMAGE,MIMETIC PEPTIDE,HEART-DISEASE,CARDIOVASCULAR-DISEASE,REDUCES INFLAMMATION,SECRETORY PHENOTYPE,atherosclerosis,endothelial damage,ionizing radiation,connexin43 hemichannels,TAT-Gap19},
  language     = {eng},
  pages        = {212},
  title        = {Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage},
  url          = {http://dx.doi.org/10.3389/fphar.2020.00212},
  volume       = {11},
  year         = {2020},
}

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