Key result
17β-Estradiol upregulates cardiac NOS expression to produce cGMP in the absence of ANP.
Why the study?
The mechanisms by which sex hormones confer cardioprotection through modulation of cardiac natriuretic peptide and nitric oxide synthase systems remain incompletely understood.
Does 17β-Estradiol alter the expression and signaling of cardiac NP and NOS systems in ANP gene-disrupted mice?
Does 17β-Estradiol alter the expression and signaling of cardiac NP and NOS systems in ANP gene-disrupted mice?
17β-Estradiol upregulates the cardiac NOS system to produce cGMP in the absence of ANP, highlighting a potential mechanism for sex-specific cardioprotection.
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.
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Wong et al. (2013) studied ANP gene-disrupted mice (ANP-/-) and wild-type (ANP+/+) (n=29). 17β-Estradiol (E2) vs. Vehicle (VEH) was evaluated on Expression of cardiac NP and NOS systems and cGMP levels. In the absence of ANP, 17β-Estradiol upregulates cardiac NOS system expression to produce cGMP, confirming the importance of the cardiac NOS system in females.
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