PDE5 inhibitor efficacy is estrogen dependent in female heart disease.
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.
Hideyuki
H
Sasaki
Takahiro
T
Nagayama
Robert M
RM
Blanton
Kinya
K
Seo
Manling
M
Zhang
Guangshuo
G
Zhu
Dong I
DI
Lee
Djahida
D
Bedja
Steven
S
Hsu
Osamu
O
Tsukamoto
Seiji
S
Takashima
Masafumi
M
Kitakaze
Michael E
ME
Mendelsohn
Richard H
RH
Karas
David A
DA
Kass
Eiki
E
Takimoto
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006331:Heart Diseases / Q000188:drug therapy* / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010052:Ovariectomy; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D016896:Treatment Outcome
D002316:Cardiotonic Agents; D004967:Estrogens; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D004958:Estradiol; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP