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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.
Summary
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.
