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J Cell Mol Med. 2017 Aug;21(8):1648-1655. doi: 10.1111/jcmm.13078. Epub 2017 Mar 17.

Cardiac cell proliferation is not necessary for exercise-induced cardiac growth but required for its protection against ischaemia/reperfusion injury.

Author information

1
Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai, China.
2
Department of Clinical laboratory, Nanxiang Hospital of Jiading, Shanghai, China.
3
Department of Geriatrics, Xuhui Central Hospital, Shanghai Clinical Center, Chinese Academy of Science, Shanghai, China.
4
Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
5
Department of Cardiology, Shanghai Yangpu District Hospital, Tongji University School of Medicine, Shanghai, China.

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.

KEYWORDS:

5-fluorouracil; exercise; ischaemia/reperfusion injury; proliferation

PMID:
28304151
PMCID:
PMC5542911
DOI:
10.1111/jcmm.13078
[Indexed for MEDLINE]
Free PMC Article

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