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Regression from pathological hypertrophy in mice is sexually dimorphic and stimulus-specific

Item Type:Article
Title:Regression from pathological hypertrophy in mice is sexually dimorphic and stimulus-specific
Creators Name:Muehleman, D.L. and Crocini, C. and Swearingen, A.R. and Ozeroff, C.D. and Leinwand, L.A.
Abstract:Pathological cardiac hypertrophy is associated with increased morbidity and mortality. Understanding the mechanisms whereby pathological cardiac growth can be reversed could have therapeutic value. Here, we show that pathways leading to regression of pathological cardiac hypertrophy are strongly dependent on the hypertrophic trigger and are significantly modified by sex. Two pathological stimuli causing hypertrophy via distinct pathways were administered to male and female mice: Angiotensin II [Ang II] or Isoproterenol [Iso]. Stimuli were removed after 7 days of treatment, and left ventricles (LV) were studied at 1, 4, and 7 days. Ang II-treated Females did not show regression after stimulus removal. Iso-treated males showed rapid LV hypertrophy regression. Somewhat surprisingly, RNAseq analysis at day 1 after removal of triggers revealed only 45 differentially regulated genes in common among all groups, demonstrating distinct responses. Ingenuity Pathway Analysis predicted strong downregulation of the TGFβ1 pathway in all groups except for Ang II-treated females. Consistently, we found significant downregulation of Smad signaling after stimulus removal including in Ang II-treated females. Additionally, the ERK1/2 pathway was significantly reduced in the groups showing regression. Finally, protein degradation pathways were significantly activated only in Iso-treated males 1 day after stimulus removal. Our data indicate that TGFβ1 downregulation may play a role in the regression of pathological cardiac hypertrophy via downregulation of the ERK1/2 pathway and activation of autophagy and proteasome activity in Iso-treated males. This work highlights that the reversal of pathological hypertrophy does not utilize universal signaling pathways and that sex potently modifies this process.
Keywords:Cardiac Hypertrophy, Regression from Hypertrophy, Heart, Animals, Mice
Source:American Journal of Physiology Heart and Circulatory Physiology
ISSN:0363-6135
Publisher:American Physiological Society
Volume:322
Number:5
Page Range:H785-H797
Date:May 2022
Official Publication:https://doi.org/10.1152/ajpheart.00644.2021
PubMed:View item in PubMed

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