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PDE5 inhibitor efficacy is estrogen dependent in female heart disease
Hideyuki Sasaki, … , David A. Kass, Eiki Takimoto
Hideyuki Sasaki, … , David A. Kass, Eiki Takimoto
Published May 16, 2014
Citation Information: J Clin Invest. 2014;124(6):2464-2471. https://doi.org/10.1172/JCI70731.
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Research Article Article has an altmetric score of 59

PDE5 inhibitor efficacy is estrogen dependent in female heart disease

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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.

Authors

Hideyuki Sasaki, Takahiro Nagayama, Robert M. Blanton, Kinya Seo, Manling Zhang, Guangshuo Zhu, Dong I. Lee, Djahida Bedja, Steven Hsu, Osamu Tsukamoto, Seiji Takashima, Masafumi Kitakaze, Michael E. Mendelsohn, Richard H. Karas, David A. Kass, Eiki Takimoto

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Figure 1

Estrogen dependence of sildenafil efficacy in female failing hearts (Gq overexpressors).

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Estrogen dependence of sildenafil efficacy in female failing hearts (Gq ...
(A) FS echocardiographic changes before and after 2 weeks of vehicle or sildenafil treatment in wild-type and Gq-overexpressing (Gq/oe) female mice subjected to sham operation [non-OVX, OVX(–)], OVX [OVX(+)], or OVX with estrogen replacement [OVX(+) + E2] (n = 7–8 per group). *P < 0.05 versus the 2-week vehicle treatment group. (B) Summary data for FS increased after 2 weeks of sildenafil (SIL) treatment (n = 7–8 per group). *P < 0.05 versus non-OVX group; †P < 0.05 versus OVX group. (C) Myocardial PKG activity. (D) PKCα activity. (E) Calcineurin (Cn) protein expression was normalized to GAPDH (n = 4–7 per group). *P < 0.05 versus the wild-type groups in non-OVX or OVX mice; †P < 0.05 versus the vehicle-without-E2 groups in non-OVX or OVX Gq/oe mice; ‡P < 0.05 versus the other groups among OVX Gq/oe mice; §P < 0.05 versus the other groups among OVX mice. P values shown are for interactions between E2 and SIL treatments (E2 × SIL); 2-way ANOVA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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