Abstract 086: Estrogen Replacement Downregulates Cardiac Angiotensin II in an ACE-independent Manner in Oophorectomized mRen2.Lewis Rats
The cardioprotective effects of estrogen are well recognized, but the mechanisms remain poorly understood. Accumulating evidence suggests that the local cardiac renin-angiotensin system (RAS) is involved in the development and progression of left ventricle (LV) remodeling and diastolic dysfunction (LVDD). Estrogen attenuates the effects of an activated circulating RAS, however, its role in regulating the cardiac RAS is unclear. We hypothesized that estrogen replacement limits the development of the LVDD phenotype after ovarian hormone loss by shifting the RAS from the pro-fibrotic angiotensin II (Ang II)/ Ang II type 1 receptor (AT1R)/converting enzyme (ACE) and aldosterone pathway to the anti-fibrotic, Ang-(1-7)/Mas/ACE2 pathway. Bilateral oophorectomy (OVX; n=17) or sham-operation (Sham; n=13) was performed in 4-week-old, female mRen2.Lewis rats. At 11 weeks of age, after the development of exacerbated hypertension, the rats were randomized and received either 17 β-estradiol (E2, 36 μg/pellet, 60 day release, n=8) or vehicle (OVX-V, n=9) for 4 weeks. E2 treatment attenuated the adverse effects of estrogen loss on tissue Doppler-derived diastolic indices, e′ and E/e′, without changing blood pressure. E2 treatment minimized the rise in circulating Ang II and aldosterone, following OVX. Chronic E2 also attenuated OVX-associated increases in cardiac Ang II, Ang-(1-7), and chymase expression, and in mast cell number as determined by real-time PCR, western blot, and immunohistochemical analyses. Neither OVX nor OVX+E2 altered cardiac expression of AT1R, or gene expression and activity of cardiac ACE. E2 treatment in OVX rats significantly decreased gene expression of MMP-9, ACE2, and Ang-(1-7) mas receptor, in comparison to sham-operated, intact and OVX littermates. In conclusion, E2 treatment inhibits upsurges in cardiac Ang II expression in the OVX-mRen2 rat, possibly in a non-ACE-dependent manner. Further studies are warranted to determine whether an E2-mediated reduction in cardiac chymase directly contributes to this response in OVX rats.
- © 2013 by American Heart Association, Inc.