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 8

Rapamycin reverses the cardiac dysfunction that occurs in Zfp36l2-KO mice.

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Rapamycin reverses the cardiac dysfunction that occurs in Zfp36l2-KO mic...
(A) Representative Western blot of p-S6S240/244 and total S6 in WT and Zfp36l2-KO hearts in nonpregnant mice (Pre) as well as pregnant mice during the third trimester of the first pregnancy (3rd) and 1 week (1 wk) and 1 month (1 mo) after delivery. (B) Summary of densitometry of Western blot analysis in A (n = 3). (C) Western blot of p-S6S240/244 in the hearts of Zfp36l2-KO and control mice in the late gestation phase, E18–E19 (n = 3). (D) Effective reduction of mTOR activity in the hearts of mice treated with rapamycin, as assessed by measurement of p-S6S240/244. (E) 2D echo image and (F) summary bar graph of EF in Zfp36l2-KO mice after treatment with rapamycin or vehicle according to the protocol in Supplemental Figure 15A (n = 10). (G) Gross examination of the hearts of Zfp36l2-KO pregnant mice treated with a vehicle or rapamycin. (H) Heart weight to tibial length (HW/TL) ratio (n = 6–9) and (I and J) markers of heart failure (Anf and Bnp) (n = 6) in Zfp36l2-KO pregnant mice treated with a vehicle or rapamycin. (K) Protein levels of the components of the ZFP36L2/P53/REDD1/SESN2/mTOR pathway in patients with PPCM and other forms of heart failure (HF). (L) Graphic representation of the pathways through which ZFP36L2 regulates mTORc1 activity. Data were analyzed by unpaired Student’s t test (F and H–J) or 1-way ANOVA with Tukey’s test for multiple group comparison (K).