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Mechanism of cardiovascular disease in premenopausal women

Award Number: R01HL155265
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $524,875 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	002	4	8/1/2024	NON-COMPETING CONTINUATION	$0
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	4	11/22/2023	NON-COMPETING CONTINUATION	$482,029
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	4	6/24/2024	NON-COMPETING CONTINUATION	$42,846
														Subtotal = $524,875

Issue Date FY: 2023 ( Subtotal = $535,587 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	3	2/11/2023	NON-COMPETING CONTINUATION	$53,558
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	3	11/21/2022	NON-COMPETING CONTINUATION	$482,029
														Subtotal = $535,587

Issue Date FY: 2022 ( Subtotal = $535,587 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	11/19/2021	NON-COMPETING CONTINUATION	$482,027
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	2	6/8/2022	NON-COMPETING CONTINUATION	$53,560
														Subtotal = $535,587

Issue Date FY: 2021 ( Subtotal = $535,587 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	1	6/17/2021	NEW	$53,558
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	12/20/2020	NEW	$482,029
														Subtotal = $535,587

Grand Total All Awards = $2,131,636

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Mechanism of cardiovascular disease in premenopausal women

Award Number: R01HL155265

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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