Mechanism of cardiovascular disease in premenopausal women

PROJECT SUMMARY Suboptimal nutrition is the leading risk factor for death and disability worldwide and accounts for accounts for more than 45% of cardiovascular death in the US. Dietary risks affect people regardless of age, sex, and sociodemographic development. However, studies investigating the cardiovascular consequences of suboptimal

diet in premenopausal women remain scarce. Notably, although compelling recent evidence indicates that women of reproductive age are more salt sensitive and prone to obesity-associated cardiovascular disease (CVD) than men, the mechanisms whereby excess salt consumption and obesity negate the premenopausal

advantage for hypertension remain unknown. In preliminary data for this application, we provide new evidence involving the steroid hormone progesterone, the adipokine leptin, as well as the “adrenal-aldosterone – endothelium-mineralocorticoid receptor (MR) axis” in both salt sensitivity and obesity related-CVD in

premenopausal women. We identified for the first time a mouse model of endogenous salt sensitivity, the Balb/C mouse, which reproduces the human phenotype and exhibits a higher salt-sensitivity in females than males. We provide data presenting lack of aldosterone suppression, MR overactivation and increased adrenal leptin

receptor expression as potential contributors to the sex-specific elevation in blood pressure in females fed a high salt diet. Concomitantly, we identified leptin as a new direct regulator of adrenal-aldosterone production and presented leptin-mediated aldosterone production and MR activation as major contributors to obesity-associated

vascular dysfunction and hypertension in females. Subsequently, we show that arteries from females are more prone to aldosterone-mediated endothelial dysfunction than that of males and that both women and female mice exhibit higher expression of the endothelial MR (ECMR) than men and male animals. Remarkably, we found that

endothelial progesterone receptor activation upregulates ECMR in females. Lastly, we show that salt sensitive female Balb/C mice have a 3-fold higher expression of ECMR than female mice on the C57Bl/6 background, which are known to be salt-resistant. Taken together, these exciting and novel findings inform the core hypothesis

of this proposal: Progesterone-induced ECMR expression and leptin-mediated adrenal aldosterone production cooperate to abolish the protective effects of female sex hormones and predispose females of reproductive age to diet-associated CVD. We will test this hypothesis in three aims. In aim 1 we will investigate the specific

contribution of adrenal leptin receptor to salt and obesity associated CVD, while in Aim 2 we will determine whether progesterone contributes to salt and obesity-associated CVD via increasing ECMR expression. Finally, in Aim 3, we will investigate using discarded human tissues whether differences in ECMR levels are responsible

for sex, strain and racial differences in salt-sensitivity via increasing endothelial ENaCα activity. We anticipate that this proposal will lead to the identification of mechanisms predisposing premenopausal women to diet- associated CVD and open new avenues for treatment.