ArticleThe Journal of clinical investigation2014
PDE5 inhibitor efficacy is estrogen dependent in female heart disease.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 79 citations in OpenAlex.
- Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials.BMC medicine · 2014Pooled it
- Cardiomyocyte GC1 Mediates Estrogenic Angiogenesis in Right Heart Remodeling.Circulation research · 2025Article
- Modeling the interplay of sex hormones in cardiac hypertrophic signaling.PLoS computational biology · 2025Article
- Review
- Underpinnings of heart failure with preserved ejection fraction in women - From prevention to improving function. A co-publication with the American Journal of Preventive Cardiology and the Journal of Cardiac Failure.American journal of preventive cardiology · 2025Article
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- Endothelial oestrogen-myocardial cyclic guanosine monophosphate axis critically determines angiogenesis and cardiac performance during pressure overload.Cardiovascular research · 2024Article
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- Targeting estrogen receptor signaling for treating heart failure.Heart failure reviews · 2024Review
- Predictors of the response to phosphodiesterase-5 inhibitors in pulmonary arterial hypertension: an analysis of the Spanish registry.Respiratory research · 2023Article
- Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Sex differences and related estrogenic effects in heart failure with preserved ejection fraction.Heart failure reviews · 2023Review
- The emerging role of estrogen's non-nuclear signaling in the cardiovascular disease.Frontiers in cardiovascular medicine · 2023Review
- Tie2-Cre-Induced Inactivation of Non-Nuclear Estrogen Receptor-α Signaling Abrogates Estrogen Protection Against Vascular Injury.JACC. Basic to translational science · 2023Article
- Sexual dimorphism in cardiac remodeling: the molecular mechanisms ruled by sex hormones in the heart.Journal of molecular medicine (Berlin, Germany) · 2022Review
- Cyclic GMP and PKG Signaling in Heart Failure.Frontiers in pharmacology · 2022Review
- Estrogen signaling as a bridge between the nucleus and mitochondria in cardiovascular diseases.Frontiers in cell and developmental biology · 2022Review
- The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates.Frontiers in cellular neuroscience · 2022Review
- The mitochondrial regulator PGC1α is induced by cGMP-PKG signaling and mediates the protective effects of phosphodiesterase 5 inhibition in heart failure.FEBS letters · 2022Article
- Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice.The Journal of clinical investigation · 2021Article
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Authors and funding
16 authors at 4 institutions in 2 countries.
Funding
Abstract
Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase Iα (PKGIα). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from Gαq-overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGIα, indicating that PKGIα mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.