An antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage

Jae-Kyung Nam, A-Ram Kim, Seo-Hyun Choi, Ji-Hee Kim, Kyu Jin Choi, Seulki Cho, Jae Won Lee, Hyun-Jai Cho, Yoo-Wook Kwon, Jaeho Cho, Kwang Seok Kim, Joon Kim, Hae-June Lee, Tae Sup Lee, Sangwoo Bae, Hyo Jeong Hong () and Yoon-Jin Lee ()
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Jae-Kyung Nam: Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences
A-Ram Kim: Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences
Seo-Hyun Choi: Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences
Ji-Hee Kim: Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences
Kyu Jin Choi: Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences
Seulki Cho: Kangwon National University
Jae Won Lee: Seoul National University Hospital
Hyun-Jai Cho: Seoul National University Hospital
Yoo-Wook Kwon: Seoul National University Hospital
Jaeho Cho: Yonsei University College of Medicine
Kwang Seok Kim: Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences
Joon Kim: Korea University
Hae-June Lee: Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences
Tae Sup Lee: Division of RI Convergence Research, Korea Institute of Radiological & Medical Sciences
Sangwoo Bae: Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences
Hyo Jeong Hong: Kangwon National University
Yoon-Jin Lee: Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial–mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart–irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.

Date: 2021
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DOI: 10.1038/s41467-021-23478-1

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