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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  ;  Yoon-Jin Lee 
 NATURE COMMUNICATIONS, Vol.12(1) : 3279, 2021-06 
Journal Title
Issue Date
Animals ; Antibiotics, Antineoplastic / toxicity ; Antibodies, Neutralizing / pharmacology* ; Cardiomyopathies / etiology ; Cardiomyopathies / genetics ; Cardiomyopathies / metabolism ; Cardiomyopathies / prevention & control* ; Cardiotoxicity / etiology ; Cardiotoxicity / genetics ; Cardiotoxicity / metabolism ; Cardiotoxicity / prevention & control* ; Case-Control Studies ; Coculture Techniques ; DNA Damage ; Disease Models, Animal ; Doxorubicin / toxicity* ; Endothelial Cells / drug effects ; Endothelial Cells / metabolism ; Endothelial Cells / pathology ; Endothelial Cells / radiation effects ; Epithelial-Mesenchymal Transition / drug effects ; Epithelial-Mesenchymal Transition / genetics ; Female ; Gamma Rays / adverse effects* ; Gene Expression Profiling ; Gene Expression Regulation ; Human Umbilical Vein Endothelial Cells / cytology ; Human Umbilical Vein Endothelial Cells / drug effects ; Human Umbilical Vein Endothelial Cells / metabolism ; Human Umbilical Vein Endothelial Cells / radiation effects ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Myocytes, Cardiac / drug effects ; Myocytes, Cardiac / metabolism ; Myocytes, Cardiac / pathology ; Myocytes, Cardiac / radiation effects ; Neural Cell Adhesion Molecule L1 / antagonists & inhibitors ; Neural Cell Adhesion Molecule L1 / genetics* ; Neural Cell Adhesion Molecule L1 / metabolism ; Signal Transduction ; Tumor Suppressor Protein p53 / deficiency ; Tumor Suppressor Protein p53 / genetics
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.
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1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Cho, Jae Ho(조재호) ORCID logo https://orcid.org/0000-0001-9966-5157
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