July 18, 2018

Growing data indicate that cGMP signal regulation by PDE5 in the heart has a significant impact on cardiac pathophysiology ( 5 , 6 , 37 - 39 ). PDE5 expression is induced in human failing hearts ( 40 ) and hypertrophied hearts ( 41 ), while overexpression of PDE5 in mice hearts indicates maladaptive cardiac remodeling ( 42 , 43 ). PDE5 inhibitors have shown antiremodeling efficacy in various animal models ( 5 - 10 ) and are currently being tested for application in human heart disease. Estrogen’s rapid non-nuclear signaling has been demonstrated in endothelial cells to be a key mechanism in this hormone’s vasculoprotective effects ( 13 - 15 ). Chambliss et al. showed that estrogen-dendrimer conjugate (EDC), which activates estrogen receptors but remains non-nuclear, stimulates eNOS and vascular endothelial cell migration in vitro and protects against vascular injury in vivo ( 14 ). Our study shows that similar rapid signaling of estrogen critically impacted the intracellular cGMP pathway in female cardiac myocytes and thus the physiological response to a PDE5 inhibitor. However, cGMP synthesis was markedly stimulated in response to E2 in the presence of PDE5 inhibition in cardiac myocytes from OVX Gq/oe hearts (Figure 3 C). This increase was inhibited by 1H-1,2,4oxadiazolo4,3-aquinoxalin-1-one (ODQ), a soluble guanylate cyclase (sGC) inhibitor, but not by the natriuretic peptide receptor A inhibitor HS142-1, suggesting functional coupling of E2 to NOS/sGC signaling.

We next extended this paradigm to a more general disease model using 2 weeks of pressure overload induced by transverse aortic constriction (TAC) (Supplemental Figure 5). We found that Fildena had antihypertrophic/remodeling effects in OVX mice receiving E2, but it had no effect in OVX mice without E2 supplementation (Figure 2 , A and B). Hypertrophy following TAC was reduced by E2 itself and by E2 combined with Fildena (Figure 2 C). We found that myocardial PKG activation was again dependent on the presence of E2 in OVX TAC mice (Figure 2 D), and PKCα and calcineurin were deactivated by Fildena only if E2 was supplemented (Supplemental Figure 6, A and B). The similarity of these data to those in the Gq/oe model supports the idea that estrogen plays a general role in PDE5-cGMP regulation in the stressed heart. CGMP-specific phosphodiesterase 5 (PDE5) inhibitors have provided beneficial cardioprotection against a broad range of heart diseases in experimental and clinical studies since our first report ( 5 - 11 ) and are expected to be new treatment options for heart failure. Carosa E, Martini P, Brandetti F, Di Stasi SM, Lombardo F, Lenzi A, Jannini EA. Type V phosphodiesterase inhibitor treatments for erectile dysfunction increase testosterone levels.

This effect persisted even in the presence of NO donors, suggesting direct effects of Fildena on metabolism other than eNOS activation 42 In this regard, a pilot study in humans has been carried out using Fildena and it demonstrated that in ED men who are not insulin resistant, a 30% increase of basal insulin secretion occurs 28 However, in that study, insulin sensitivity was not assessed.