Sex, estrogen and the role of cardiac vasoactive gene systems in the modulation of cardiac hypertrophy in ANP gene-disrupted mice

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Wong, Philip
Estrogen , Heart , Nitric Oxide Synthase , Mouse , Atrial Natriuretic Peptide
Sex dimorphism in the prevalence, onset, development and progression of cardiovascular disease (CVD) is well recognized. Sex-specific differences in adaptation to cardiac pathological progressions such as cardiac hypertrophy (CH), and the extent to which they are attributable to sex hormones requires further delineation. The objective of this dissertation was to determine which cardiac vasoactive systems are responsible for sex-specific differences in CH modulation using the atrial natriuretic peptide gene-disrupted (ANP-/-) mouse model. First, sex-specific differences in the expression of the cardiac natriuretic peptide (NP) and nitric oxide synthase (NOS) systems were evaluated. Next, the influence of 17β-Estradiol (E2) on the expression and signaling of the cardiac NP and NOS systems was determined in ovariectomized (OVX) female ANP+/+ and ANP-/- mice. Finally, sex-specific differences in cardiac adaptation to Angiotensin II (ANGII) pressure overload were elucidated in male and intact female ANP+/+ and ANP-/- mice. These studies revealed that males predominantly use the NP system and females predominantly use the NOS system. Sex-specific differences in the cardiac NOS system were further enhanced by E2 in OVX female ANP+/+ and ANP-/- mice. In the female ANP-/- mouse, E2 was found to signal through the NOS system to significantly increase plasma cGMP. Finally, male and female differences were demonstrated in the sex-specific patterns of cardiac vasoactive gene system expression and development of cardiac dysfunction in response to ANGII treatment. Sex dimorphism was observed in the expression of BNP and NPR-A in male and female ANP-/- mice treated with ANGII. Female ANP+/+ and ANP-/- ANGII-treated mice exhibited elevated E/E’ ratios that were not found to the same extent in genotype matched ANGII-treated male mice, demonstrating that female mice developed ANGII-mediated mild left ventricle diastolic dysfunction. Based on the results of this dissertation, we conclude that sex-specific differences do indeed exist in the cardiac adaptation to pathological stresses. These data support the understanding that a progression towards sex-specific CVD treatments is warranted, with a particular emphasis on the potential benefits of female-specific targeting of the cardiac NOS system.
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