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 3

RNA-Seq of H9c2 cells treated with Zfp36l2 or control siRNA.

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RNA-Seq of H9c2 cells treated with Zfp36l2 or control siRNA. (A) Volcano...
(A) Volcano plot of transcripts from the Zfp36l2 KD versus control RNA-Seq experiment. Transcripts were normalized to Actb and Hprt1, and depicted are the –log10 transformation of the adjusted P values versus the “beta value” estimated by sleuth-ALR. Highlighted genes include Zfp36l2 to confirm the KD, and other genes in the mTOR signaling pathway that had 1 major transcript significantly upregulated or downregulated. (B) Heatmap plot of differentially expressed transcripts from the mTOR signaling pathway estimated with Zfp36l2 KD (n = 6).