title: Cardiac cell proliferation is not necessary for exercise-induced cardiac growth but required for its protection against ischaemia/reperfusion injury.
abstract: The adult heart retains a limited ability to regenerate in response to injury. Although exercise can reduce cardiac ischaemia/reperfusion (I/R) injury, the relative contribution of cardiac cell proliferation including newly formed cardiomyocytes remains unclear. A 4-week swimming murine model was utilized to induce cardiac physiological growth. Simultaneously, the antineoplastic agent 5-fluorouracil (5-FU), which acts during the S phase of the cell cycle, was given to mice via intraperitoneal injections. Using EdU and Ki-67 immunolabelling, we showed that exercise-induced cardiac cell proliferation was blunted by 5-FU. In addition, the growth of heart in size and weight upon exercise was unaltered, probably due to the fact that exercise-induced cardiomyocyte hypertrophy was not influenced by 5-FU as demonstrated by wheat germ agglutinin staining. Meanwhile, the markers for pathological hypertrophy, including ANP and BNP, were not changed by either exercise or 5-FU, indicating that physiological growth still developed in the presence of 5-FU. Furthermore, we showed that CITED4, a key regulator for cardiomyocyte proliferation, was blocked by 5-FU. Meanwhile, C/EBPβ, a transcription factor responsible for both cellular proliferation and hypertrophy, was not altered by treatment with 5-FU. Importantly, the effects of exercise in reducing cardiac I/R injury could be abolished when cardiac cell proliferation was attenuated in mice treated with 5-FU. In conclusion, cardiac cell proliferation is not necessary for exercise-induced cardiac physiological growth, but it is required for exercise-associated protection against I/R injury.
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Bei
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, China.
authors.forename: Siyi
authors.initials: S
authors.lastname: Fu
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, China.|Department of Clinical laboratory, Nanxiang Hospital of Jiading, Shanghai, China.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Chen
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, China.|Department of Geriatrics, Xuhui Central Hospital, Shanghai Clinical Center, Chinese Academy of Science, Shanghai, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, China.
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Pujiao
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Shanghai Yangpu District Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Cardiology, Shanghai Yangpu District Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Hongbao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Che
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xu
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology*; D005786:Gene Expression Regulation; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal; D016196:S Phase / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction; D013550:Swimming; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; C499189:Cited4 protein, mouse; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D014157:Transcription Factors; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D005472:Fluorouracil
keywords: 5-fluorouracil; exercise; ischaemia/reperfusion injury; proliferation