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, Richard H. Karas, Issei Komuro

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish
Pages (from-to)282-295
Number of pages14
JournalJACC: Basic to Translational Science
Volume5
Issue number3
DOIs
StatePublished - Mar 2020
Externally publishedYes

Keywords

  • cyclic GMP
  • estradiol
  • heart failure
  • non-nuclear signaling
  • sGC stimulator

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