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缝隙连接蛋白 43 通道及其通过 IP3/Ca2+、ATP 和 ROS/NO 传递的信号将辐射诱导的 DNA 损伤传递至未辐射的脑微血管内皮细胞。

Cx43 channels and signaling via IP/Ca, ATP, and ROS/NO propagate radiation-induced DNA damage to non-irradiated brain microvascular endothelial cells.

机构信息

Physiology group, Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium.

Infinity Lab, IBiTech-MEDISIP, Department of Electronics and Information Systems, Ghent University, Ghent, Belgium.

出版信息

Cell Death Dis. 2020 Mar 18;11(3):194. doi: 10.1038/s41419-020-2392-5.

DOI:10.1038/s41419-020-2392-5
PMID:32188841
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7080808/
Abstract

Radiotherapeutic treatment consists of targeted application of radiation beams to a tumor but exposure of surrounding healthy tissue is inevitable. In the brain, ionizing radiation induces breakdown of the blood-brain barrier by effects on brain microvascular endothelial cells. Damage from directly irradiated cells can be transferred to surrounding non-exposed bystander cells, known as the radiation-induced bystander effect. We investigated involvement of connexin channels and paracrine signaling in radiation-induced bystander DNA damage in brain microvascular endothelial cells exposed to focused X-rays. Irradiation caused DNA damage in the directly exposed area, which propagated over several millimeters in the bystander area. DNA damage was significantly reduced by the connexin channel-targeting peptide Gap26 and the Cx43 hemichannel blocker TAT-Gap19. ATP release, dye uptake, and patch clamp experiments showed that hemichannels opened within 5 min post irradiation in both irradiated and bystander areas. Bystander signaling involved cellular Ca dynamics and IP, ATP, ROS, and NO signaling, with Ca, IP, and ROS as crucial propagators of DNA damage. We conclude that bystander effects are communicated by a concerted cascade involving connexin channels, and IP/Ca, ATP, ROS, and NO as major contributors of regenerative signal expansion.

摘要

放射治疗包括将辐射束靶向应用于肿瘤，但周围健康组织的暴露是不可避免的。在大脑中，电离辐射通过对脑微血管内皮细胞的作用导致血脑屏障的破坏。直接照射细胞的损伤可以通过所谓的辐射诱导旁观者效应转移到周围未暴露的旁观者细胞。我们研究了缝隙连接通道和旁分泌信号在聚焦 X 射线照射的脑微血管内皮细胞中辐射诱导旁观者 DNA 损伤中的作用。照射导致直接暴露区域的 DNA 损伤，该损伤在旁观者区域传播数毫米。缝隙连接通道靶向肽 Gap26 和 Cx43 半通道阻断剂 TAT-Gap19 显著减少了 DNA 损伤。ATP 释放、染料摄取和膜片钳实验表明，照射后 5 分钟内，照射区和旁观者区的半通道均开放。旁观者信号涉及细胞 Ca 动力学和 IP、ATP、ROS 和 NO 信号，Ca、IP 和 ROS 是 DNA 损伤的关键传播者。我们得出结论，旁观者效应是通过涉及缝隙连接通道的协同级联传递的，而 IP/Ca、ATP、ROS 和 NO 是再生信号扩展的主要贡献者。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/f656011b9023/41419_2020_2392_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/25d1c49a212d/41419_2020_2392_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/f08fe58a6038/41419_2020_2392_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/44c15eef6c5d/41419_2020_2392_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/e62acc15dab5/41419_2020_2392_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/1ac03504ebae/41419_2020_2392_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/40ec13944e55/41419_2020_2392_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/fc02959f8cea/41419_2020_2392_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/f656011b9023/41419_2020_2392_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/25d1c49a212d/41419_2020_2392_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/f08fe58a6038/41419_2020_2392_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/44c15eef6c5d/41419_2020_2392_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/e62acc15dab5/41419_2020_2392_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/1ac03504ebae/41419_2020_2392_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/40ec13944e55/41419_2020_2392_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/fc02959f8cea/41419_2020_2392_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5478/7080808/f656011b9023/41419_2020_2392_Fig8_HTML.jpg

相似文献

[1]
Cx43 channels and signaling via IP/Ca, ATP, and ROS/NO propagate radiation-induced DNA damage to non-irradiated brain microvascular endothelial cells.

Cell Death Dis. 2020-3-18

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
Cx43 enhances response to BRAF/MEK inhibitors by reducing DNA repair capacity.

Nat Commun. 2025-7-4

[2]
Coordination of innate immune responses by connexins.

Front Immunol. 2025-5-22

[3]
The Double-Edged Effect of Connexins and Pannexins of Glial Cells in Central and Peripheral Nervous System After Nerve Injury.

Mol Neurobiol. 2025-5-1

[4]
The effect of CGRP and SP and the cell signaling dialogue between sensory neurons and endothelial cells.

Biol Res. 2024-9-11

[5]
Simulation of gap junction formation reveals critical role of Cys disulfide redox state in connexin hemichannel docking.

Cell Commun Signal. 2024-3-18

[6]
Iron overload induced submandibular glands toxicity in gamma irradiated rats with possible mitigation by hesperidin and rutin.

BMC Pharmacol Toxicol. 2024-2-27

[7]
Neurotoxicity-sparing radiotherapy for brain metastases in breast cancer: a narrative review.

Front Oncol. 2024-2-2

[8]
SARS-CoV-2 spike protein S1 activates Cx43 hemichannels and disturbs intracellular Ca dynamics.

Biol Res. 2023-10-25

[9]
Astragaloside IV protects LO2 cells from oxidative damage caused by radiation-induced bystander effect through Akt/Nrf2 pathway.

Toxicol Res (Camb). 2023-7-6

[10]
Role of Cx43 in iPSC-CM Damage Induced by Microwave Radiation.

Int J Mol Sci. 2023-8-8

本文引用的文献

[1]
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Trends Mol Med. 2018-11-10

[2]
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Pharmacol Rev. 2017-10

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IP3, still on the move but now in the slow lane.

Sci Signal. 2016-11-8

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Cancer Lett. 2013-10-15

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Diffusion of nitric oxide across cell membranes of the vascular wall requires specific connexin-based channels.

Neuropharmacology. 2013-12

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Low-dose gamma irradiation enhances superoxide anion production by nonirradiated cells through TGF-β1-dependent bystander signaling.

Radiat Res. 2013-3-6

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Cell Tissue Res. 2012-9-1

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Biochim Biophys Acta. 2013-1

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Dynamics of γH2AX formation and elimination in mammalian cells after X-irradiation.

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Reactive oxygen species-induced release of signalling factors in irradiated cells triggers membrane signalling and calcium influx in bystander cells.

Int J Radiat Biol. 2011-2-7

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