ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice
Hidemichi Kouzu, … , Perry J. Blackshear, Hossein Ardehali
Hidemichi Kouzu, … , Perry J. Blackshear, Hossein Ardehali
Published March 22, 2022
Citation Information: J Clin Invest. 2022;132(10):e154491. https://doi.org/10.1172/JCI154491.
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Research Article Cardiology Cell biology

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

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 cardiomyocyte 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 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.

Authors

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

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Figure 4

Zfp36l2 deletion in the heart causes activation of the mTORc1 pathway.

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Zfp36l2 deletion in the heart causes activation of the mTORc1 pathway. ...
(A) Representative Western blot of heart extracts from control and Zfp36l2-KO mice, demonstrating increased mTOR activity with Zfp36l2 deletion. (B–D) Summary of densitometry of Western blot analyses in A, (B) demonstrating increased p-P70S6KT389 (n = 10–11), (C) decreased p-AKTS473 (n = 9–10), and (D) no change in p-AMPKT172 (n = 9–10). (E) Representative Western blot of H9c2 cells treated with control or Zfp36l2 siRNA in the presence and absence of insulin and 10 nM rapamycin. (F and G) Summary of densitometry of Western blot analysis in E (n = 4). (H) Representative Western blot of H9c2 cells treated with control or Tsc2 siRNA with or without concurrent Zfp36l2 KD. (I) Summary of densitometry of Western blot for p-P70S6KT389 in H (n = 4). Data were analyzed by unpaired Student’s t test (B–D) or 2-way ANOVA with Tukey’s test for multiple group comparison (F, G, and I).