Estrogen Receptor-α Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy

Nobuaki Fukuma; Eiki Takimoto; Kazutaka Ueda; Pangyen Liu; Miyu Tajima; Yu Otsu; Taro Kariya; Mutsuo Harada; Haruhiro Toko; Kaori Koga; Robert M Blanton Jr; Richard H Karas; Issei Komuro

doi:10.1016/j.jacbts.2019.12.009

Estrogen Receptor-α Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy

JACC Basic Transl Sci. 2020 Mar 4;5(3):282-295. doi: 10.1016/j.jacbts.2019.12.009. eCollection 2020 Mar.

Authors

Affiliations

¹ Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
³ Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
⁴ Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts.

Abstract

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.

Keywords: E2, estradiol; ECs, endothelial cells; EDC, estrogen dendrimer conjugate; ER, estrogen receptor; LV, left ventricular; NO, nitric oxide; PDE5i, phosphodiesterase 5 inhibitor; PKG, cGMP-dependent protein kinase G; PaPE, pathway-preferential estrogen; TAC, transverse aortic constriction; VO2, oxygen consumption rate; cGMP, cyclic guanosine monophosphate; cyclic GMP; eNOS, endothelial nitric oxide synthase; estradiol; heart failure; non-nuclear signaling; sGC stimulator; sGC, soluble guanylate cyclase.

Abstract

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