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ResearchIn-Press PreviewCardiologyCell biology Open Access | 10.1172/JCI154491

ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peri-partum cardiomyopathy in mice

Hidemichi Kouzu,1 Yuki Tatekoshi,1 Hsiang-Chun Chang,1 Jason S. Shapiro,2 Warren A. McGee,1 Adam De Jesus,2 Issam Ben-Sahra,3 Zoltan Arany,4 Jonathan Leor,5 Chunlei Chen,2 Perry J. Blackshear,6 and Hossein Ardehali1

1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

Find articles by Chen, C. in: PubMed | Google Scholar

1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

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1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

2Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States of America

3Department of Biochemistry, Northwestern University, Chicago, United States of America

4Department of Medicine, University of Pennsylvania, Philadelphia, United States of America

5Cardiovascular Research Institute, Tel Aviv University and Sheba Medical Center, Tel Aviv, Israel

6Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, United States of America

Find articles by Ardehali, H. in: PubMed | Google Scholar |

Published March 22, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI154491.
Copyright © 2022, Kouzu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 22, 2022 - Version history
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Abstract

Pregnancy is associated with substantial physiological changes of the heart, and disruptions in these processes can lead to peripartum-cardiomyopathy (PPCM). The molecular processes that cause physiological and pathological changes in the heart during pregnancy are not well characterized. Here, we show that mTORc1 was activated in pregnancy to facilitate cardiac enlargement that was reversed after delivery in mice. mTORc1 activation in pregnancy was negatively regulated by the mRNA-destabilizing-protein ZFP36L2 through its degradation of Mdm2 mRNA and P53 stabilization, leading to increased SESN2 and REDD1 expression. This pathway impeded uncontrolled cardiomyocytes hypertrophy during pregnancy, and mice with cardiac-specific Zfp36l2 deletion developed rapid cardiac dysfunction after delivery, while prenatal treatment of these mice with rapamycin improved post-partum cardiac function. Collectively, these data provide a novel pathway for the regulation of mTORc1 through mRNA stabilization of a P53 ubiquitin ligase. This pathway was critical for normal cardiac growth during pregnancy, and its reduction led to PPCM-like adverse remodeling in mice.

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Version history
  • Version 1 (March 22, 2022): In-Press Preview
  • Version 2 (May 16, 2022): Electronic publication
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