Abstract 12848: Estrogen Potentiates Cardiac Anti-Hypertrophy/Remodeling From Cyclic GMP-PDE5 Inhibition
Background PDE5 inhibitor sildenafil (SIL) activates cGMP-PKG and ameliorates cardiac hypertrophy/remodeling in male mice pressure-overload model, associated with de-activation of Gq signaling. Anti-remodeling effect from SIL was also reported in a small group of human heart failure patients, and multi-center clinical trial is on-going. However, its efficacy in female needs to be determined, given cGMP signaling is coupled to estrogen. This study examines the impact of estrogen on SIL-cGMP mediated cardio-protection, using Gαq transgenic mice (Gq TG) and culture cardiac myocytes.
Methods and Results First, we examined SIL efficacy (oral 100mg/kg/day for 2 weeks) in male and female Gq TG at the age of 7 weeks. There was no significant gender difference at baseline in cardiac function or anatomy (Male FS: 35.7±0.29%, ESD: 2.2±0.05mm and Female FS:35.0±0.8%, ESD: 2.2±0.1mm) as assessed by echocardiography. The SIL response was greater in female mice (n=7) (FS: 46.5±1.48%, ESD: 1.89±0.10mm) than male mice (n=7) (FS: 40.8±0.96%, ESD: 2.24±0.08mm). Myocardial mRNA levels for BNP and MCIP (modulatory calcineurin-interacting protein, reflecting calcineurin activity) were higher in vehicle-treated male than in female, which were reduced by SIL. Next, we tested whether the enhanced SIL efficacy depends on estrogen by examining mice exposed to ovariectomy. Importantly, SIL efficacy was markedly diminished after ovariectomy (n=8) (FS: 40.7±1.81%, ESD: 2.15±0.13mm), but was restored with estrogen replacement (n=9) (FS: 45.1±0.75%, ESD: 1.90±0.08mm). In cultured rat cardiac myocytes, 17β-estradiol (E2, 1 nM) and SIL (1 µM) similarly inhibited phenylephrine-induced (20 µM for 48 hours) hypertrophy as assessed by cell surface area and BNP expression. Consistent with the in vivo observation, combined E2 and SIL significantly enhanced anti-hypertrophic effects. These effects were absent by a PKG inhibitor (Rp-8-Br-PET-cGMPs, 30µM) or by an estrogen receptor antagonist (ICI182,780, 1 µM).
Conclusions Our results suggest the pivotal role for estrogen in anti-hypertrophy/remodeling by SIL. Considering the high incidence of cardiovascular disease in postmenopausal women, these findings are of high clinical importance.
- © 2011 by American Heart Association, Inc.