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Regression from pathological hypertrophy in mice is sexually dimorphic and stimulus specific
Deanna L Muehleman1,2, Claudia Crocini1,2,3,4, Alison R Swearingen2
1BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado.
Abstract:
Pathological cardiac hypertrophy is associated with increased morbidity and mortality. Understanding the mechanisms whereby pathological cardiac growth can be reversed could be of 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 (LVs) 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 the 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. In addition, 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 use universal signaling pathways and that sex potently modifies this process.NEW & NOTEWORTHY Pathological cardiac hypertrophy is a major risk factor for mortality and is thought to be largely irreversible in many individuals. Although cardiac hypertrophy itself has been studied extensively, very little is understood about its regression. It is important that we have a better understanding of mechanisms leading to regression, why this process is not reversible in some individuals and that sex differences need to be considered when contemplating therapies.
Insights
Cardiac hypertrophy regression depends on the trigger and sex. Isoproterenol-induced hypertrophy regressed in males, but not in females, highlighting distinct sex-specific pathways.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Physiology
Background:
- Pathological cardiac hypertrophy significantly increases morbidity and mortality.
- Understanding mechanisms of cardiac hypertrophy reversal is crucial for therapeutic development.
- Cardiac hypertrophy regression is poorly understood and often considered irreversible.
Purpose of the Study:
- To investigate the signaling pathways involved in the regression of pathological cardiac hypertrophy.
- To determine if these regression pathways are conserved across different hypertrophic triggers.
- To elucidate the role of sex in modulating cardiac hypertrophy regression.
Main Methods:
- Male and female mice received either angiotensin II (ANG II) or isoproterenol (Iso) for 7 days.
- Stimuli were removed, and left ventricles (LVs) were analyzed at 1, 4, and 7 days post-removal.
- RNA sequencing (RNAseq) and Ingenuity Pathway Analysis (IPA) were used to assess gene expression and signaling pathways.
Main Results:
- Cardiac hypertrophy regression was trigger- and sex-dependent; ANG II-induced hypertrophy did not regress in females, while Iso-induced hypertrophy regressed in males.
- RNAseq revealed distinct molecular responses to stimulus removal, with only 45 common differentially regulated genes across all groups.
- Transforming growth factor-beta 1 (TGFβ1) and Extracellular signal-regulated kinase 1/2 (ERK1/2) pathways were downregulated in regressing groups, while protein degradation pathways (autophagy, proteasome) were activated in Iso-treated males.
Conclusions:
- Regression of pathological cardiac hypertrophy is not a universal process and is significantly influenced by the initial hypertrophic stimulus and sex.
- TGFβ1 downregulation, potentially via ERK1/2 inhibition and activation of protein degradation, may mediate hypertrophy regression in Iso-treated males.
- These findings underscore the need to consider sex as a critical factor in developing therapies for cardiac hypertrophy reversal.
