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

ABSTRACT: Using genetically engineered mice lacking estrogen receptor-? non-nuclear signaling, this study demonstrated that estrogen receptor-? 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.

SUBMITTER: Fukuma N

PROVIDER: S-EPMC7091505 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Fukuma Nobuaki N Takimoto Eiki E Ueda Kazutaka K Liu Pangyen P Tajima Miyu M Otsu Yu Y Kariya Taro T Harada Mutsuo M Toko Haruhiro H Koga Kaori K Blanton Robert M RM Karas Richard H RH Komuro Issei I

JACC. Basic to translational science 20200304 3

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. T ...[more]

PMID: 32215350

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Project description:BackgroundA pandemic outbreak of COVID-19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, "cytokines storm," that causes the systemic complications of COVID-19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability.ObjectivesNumerous clinical and experimental studies have revealed a role for the nitric oxide (NO)-cyclic GMP-phosphodiesterase type 5 (PDE5) pathway in modulating low-grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti-inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID-19 disease.Materials and methodsWe performed a systematic review of all evidence documenting any involvement of the NO-cGMP-PDE5 axis in the pathophysiology of COVID-19, presenting the ongoing clinical trials aimed at modulating this axis, including our own "silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID-19 (DEDALO trial)."ResultsThe reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID-19 by (i) counteracting the Ang-II-mediated downregulation of AT-1 receptor; (ii) acting on monocyte switching, thus reducing pro-inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage-necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications.Discussion and conclusionIf the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID-19 in developing countries.

Dataset Information

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

Publications

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

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