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 journalArticlepeer-review

5 Scopus citations


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 languageEnglish (US)
Article numbere154491
JournalJournal of Clinical Investigation
Issue number10
StatePublished - May 16 2022

ASJC Scopus subject areas

  • Medicine(all)


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