Author + information
- Received July 18, 2019
- Revision received December 18, 2019
- Accepted December 18, 2019
- Published online March 23, 2020.
- Nobuaki Fukuma, MD, PhDa,
- Eiki Takimoto, MD PhDa,d,∗ (, )
- Kazutaka Ueda, MD, PhDa,
- Pangyen Liu, MDa,
- Miyu Tajima, MDa,
- Yu Otsu, MD, PhDa,
- Taro Kariya, MD, PhDa,
- Mutsuo Harada, MD, PhDa,
- Haruhiro Toko, MD, PhDa,
- Kaori Koga, MD, PhDb,
- Robert M. Blanton Jr., MDc,
- Richard H. Karas, MD, PhDc and
- Issei Komuro, MD, PhDa,∗ ()
- aDepartment of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- bDepartment of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
- cMolecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts
- dDivision of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland
- ↵∗Address for correspondence:
Dr. Eiki Takimoto OR Dr. Issei Komuro, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan.
• The role of ERα non-nuclear signaling in female heart failure was investigated, using a novel mouse line in which ERα non-nuclear signaling was selectively disrupted by inhibiting the interaction between ERα and striatin, a scaffold protein residing at caveolae.
• ERα non-nuclear signaling was linked to myocardial PKG activity in female hearts and ameliorated cardiac maladaptive remodeling induced by pressure overload.
• ERα non-nuclear signaling was indispensable to the therapeutic efficacy of cGMP-PDE5 inhibition in heart failure but not to that of sGC stimulation.
• sGC stimulation potently ameliorated cardiac remodeling, regardless of estrogen conditions, in sharp contrast to PDE5 inhibition.
• The study provided the first in vivo evidence for the role of ERα non-nuclear signaling in heart failure, linking it to cGMP-PKG pathways. The data also supported the advantage of sGC stimulation over PDE5 inhibition as a potential therapeutic strategy in treating heart failure in post-menopausal women, highlighting the need for female-specific therapeutic strategies.
Using genetically engineered mice lacking estrogen receptor-α non-nuclear signaling, this study demonstrated that estrogen receptor−α non-nuclear signaling activated myocardial cyclic guanosine monophosphate-dependent protein kinase G and conferred protection against cardiac remodeling induced by pressure overload. This pathway was indispensable to the therapeutic efficacy of cyclic guanosine monophosphate−phosphodiesterase 5 inhibition but not to that of soluble guanylate cyclase stimulation. These results might partially explain the equivocal results of phosphodiesterase 5 inhibitor efficacy and also provide the molecular basis for the advantage of using a soluble guanylate cyclase simulator as a new therapeutic option in post-menopausal women. This study also highlighted the need for female-specific therapeutic strategies for heart failure.
This work was supported by the National Institutes of Health (grant HL-093432), the American Heart Association (grant-in-aid 11GRNT7700071), the SENSHIN Medical Research Foundation; and the TAKEDA Science Foundation. Dr. Takimoto was supported by a Grant-in-Aid for Scientific Research (25893044). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received July 18, 2019.
- Revision received December 18, 2019.
- Accepted December 18, 2019.
- 2020 The Authors