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

Hidemichi Kouzu; Yuki Tatekoshi; Hsiang Chun Chang; Jason S. Shapiro; Warren A. McGee; Adam De Jesus; Issam Ben-Sahra; Zoltan Arany; Jonathan Leor; Chunlei Chen; Perry J. Blackshear; Hossein Ardehali

doi:10.1172/JCI154491

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

Hidemichi Kouzu, Yuki Tatekoshi, Hsiang Chun Chang, Jason S. Shapiro, Warren A. McGee, Adam De Jesus, Issam Ben-Sahra, Zoltan Arany, Jonathan Leor, Chunlei Chen, Perry J. Blackshear, Hossein Ardehali^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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 mRNAdestabilizing protein ZFP36L2 through its degradation of Mdm2 mRNA and P53 stabilization, leading to increased SESN2 and REDD1 expression. This pathway impeded uncontrolled cardiomyocyte hypertrophy during pregnancy, and mice with cardiacspecific Zfp36l2 deletion developed rapid cardiac dysfunction after delivery, while prenatal treatment of these mice with rapamycin improved postpartum cardiac function. Collectively, these data provide what we believe to be 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.

Original language	English (US)
Article number	e154491
Journal	Journal of Clinical Investigation
Volume	132
Issue number	10
DOIs	https://doi.org/10.1172/JCI154491
State	Published - May 16 2022

Funding

This work was supported by the Northwestern University Sanger Sequencing Facility. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by National Cancer Institute P30-CA060553, which was awarded to the Robert H. Lurie Comprehensive Cancer Center. RNA-Seq experiments were supported by the Northwestern University NUseq Core. The graphic abstract was created with BioRender.com. This work was made possible through core services and support from the Northwestern University George M. O\u2019Brien Kidney Research Core Center (NU GoKid-ney) and an NIH/National Institute of Diabetes and Digestive and Kidney Diseases funded program (P30 DK114857). Funding for this work was provided from the National Heart, Lung, and Blood Institute (HL127646, HL140973, HL140927, and HL138982); a Leducq grant awarded to HA; and the Intramural Research Program of the National Institute of Environmental Health Sciences, a component of the NIH (to PJB). HK was supported by American Heart Association grant 16POST31020036 and the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad.

ASJC Scopus subject areas

General Medicine

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Kouzu, H., Tatekoshi, Y., Chang, H. C., Shapiro, J. S., McGee, W. A., De Jesus, A., Ben-Sahra, I., Arany, Z., Leor, J., Chen, C., Blackshear, P. J., & Ardehali, H. (2022). ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice. Journal of Clinical Investigation, 132(10), Article e154491. https://doi.org/10.1172/JCI154491

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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 mRNAdestabilizing protein ZFP36L2 through its degradation of Mdm2 mRNA and P53 stabilization, leading to increased SESN2 and REDD1 expression. This pathway impeded uncontrolled cardiomyocyte hypertrophy during pregnancy, and mice with cardiacspecific Zfp36l2 deletion developed rapid cardiac dysfunction after delivery, while prenatal treatment of these mice with rapamycin improved postpartum cardiac function. Collectively, these data provide what we believe to be 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.",

author = "Hidemichi Kouzu and Yuki Tatekoshi and Chang, {Hsiang Chun} and Shapiro, {Jason S.} and McGee, {Warren A.} and {De Jesus}, Adam and Issam Ben-Sahra and Zoltan Arany and Jonathan Leor and Chunlei Chen and Blackshear, {Perry J.} and Hossein Ardehali",

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AU - McGee, Warren A.

AU - De Jesus, Adam

AU - Ben-Sahra, Issam

AU - Arany, Zoltan

AU - Leor, Jonathan

AU - Chen, Chunlei

AU - Blackshear, Perry J.

AU - Ardehali, Hossein

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

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