Contribution of Estrogen to Sex Dimorphic Expression of Cardiac Natriuretic Peptide and Nitric Oxide Synthase Systems in ANP Gene-Disrupted Mice

摘要

Background: Sex dimorphism in the prevalence, onset, development and progression of cardiovascular disease (CVD) is well recognized, but the mechanisms whereby sex hormones are believed to confer cardioprotection are still not fully understood. Objective: This study more closely delineates the effect of 17β-Estradiol (E2) on the expression and signaling of the cardiac NP and NOS systems, well-known cardioprotective modulators of the cardiac hypertrophy (CH) response, that both contribute to downstream production of cyclic guanosine 3’,5’-monophosphate (cGMP). Materials and Methods: Ovariectomized (OVX) female ANP+/+ and ANP-/- mice, 6 - 7 weeks old, were subjected to a five-week treatment with E2 (100 μg/100 μL/day) or vehicle (VEH). Left ventricle from these treatment groups, along with that from age-matched male ANP+/+ and ANP-/- mice was used to assess expression of these systems by real-time quantitative PCR (qPCR). Left ventricle tissue and plasma cGMP were measured by enzyme immunoassay to assess alterations in resultant downstream signaling. Results: NP system expression was unchanged across genotype, sex and E2 treatment. Sex-specific differences in NOS system expression were observed;female mice showed an increased expression of NOS system genes that were significantly elevated in all but one of the E2 treatment groups. Left ventricle tissue cGMP remained unchanged across genotype, sex and E2 treatment. Plasma cGMP levels were unchanged in ANP+/+ treatment groups. In ANP-/- treatment groups, plasma cGMP in the female OVX-E2 mice was significantly higher compared to male and female OVX-VEH mice. Conclusion: These findings demonstrate that in the absence of ANP, E2 upregulates cardiac NOS system expression to produce cGMP. This study confirms the importance of the cardiac NOS system in females;this particular system may be a promising future target for sex-specific treatments and therapies for CVD in women.