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Estrogen Receptor-α Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy
Nobuaki Fukuma1, Eiki Takimoto1,2, Kazutaka Ueda1
1Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
JACC. Basic to Translational Science
|March 28, 2020
Summary
Estrogen receptor-α non-nuclear signaling protects against heart remodeling by activating protein kinase G. This pathway is crucial for phosphodiesterase 5 inhibitor efficacy, suggesting female-specific heart failure treatments.
Area of Science:
- Cardiovascular biology
- Endocrinology
- Molecular signaling
Background:
- Cardiac remodeling is a significant factor in heart failure progression.
- Estrogen receptor-α (ERα) plays a role in cardiovascular health.
- Non-nuclear ERα signaling pathways are increasingly recognized for their physiological importance.
Purpose of the Study:
- To investigate the role of non-nuclear ERα signaling in protection against pressure overload-induced cardiac remodeling.
- To elucidate the downstream molecular targets of non-nuclear ERα signaling in the heart.
- To determine the impact of non-nuclear ERα signaling on the efficacy of phosphodiesterase 5 (PDE5) inhibitors and soluble guanylate cyclase (sGC) stimulators.
Main Methods:
- Utilized genetically engineered mice lacking functional non-nuclear ERα signaling.
- Induced cardiac remodeling via pressure overload models.
- Assessed myocardial cyclic guanosine monophosphate-dependent protein kinase G (PKG) activation.
- Evaluated the effects of PDE5 inhibition and sGC stimulation on cardiac remodeling and PKG activity.
Main Results:
- Non-nuclear ERα signaling activated myocardial PKG.
- This pathway was essential for protection against pressure overload-induced cardiac remodeling.
- The therapeutic efficacy of PDE5 inhibition was dependent on non-nuclear ERα signaling.
- Conversely, sGC stimulation's efficacy was independent of this pathway.
Conclusions:
- Non-nuclear ERα signaling is a critical mediator of cardioprotection via PKG activation.
- This finding may explain variable responses to PDE5 inhibitors and supports sGC stimulators as a therapeutic option for post-menopausal women.
- Highlights the necessity for sex-specific therapeutic strategies in managing heart failure.
Keywords:
E2, estradiolECs, endothelial cellsEDC, estrogen dendrimer conjugateER, estrogen receptorLV, left ventricularNO, nitric oxidePDE5i, phosphodiesterase 5 inhibitorPKG, cGMP-dependent protein kinase GPaPE, pathway-preferential estrogenTAC, transverse aortic constrictionVO2, oxygen consumption ratecGMP, cyclic guanosine monophosphatecyclic GMPeNOS, endothelial nitric oxide synthaseestradiolheart failurenon-nuclear signalingsGC stimulatorsGC, soluble guanylate cyclaseMore Related Videos
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