(Verbatim from the application): Hypertension is a major contributor to cardiovascular disease, the leading cause of death in US women. Most studies of hypertension have focused on men. Women have a lower incidence of hypertension until age 50 at which time, the incidence of hypertension in women becomes greater than that in men. Since age 50 is the average age of menopause in US women, this observation suggests that ovarian steroids, present in the premenopausal state, mask genetic predisposition to hypertension and that with loss of these steroids at menopause, genetic predisposition to hypertension becomes manifest. We have shown that a specific intermediate phenotype of essential hypertension is associated with polymorphisms of the angiotensinogen gene which result in greater tissue activity of the renin-angiotensin-aldosterone system (RAAS) as a possible cause of hypertension. This phenotype is uncommon in premenopausal women compared to age-matched men but the frequency of this phenotype increases at menopause becoming equal in men and women. Estradiol has major effects on many of the genes of the RAAS and therefore is a prime candidate for modulating the expression of genotype and being responsible for the change in phenotype frequency in pre versus postmenopausal women. The overall objectives of this proposal are to: 1) demonstrate a difference in frequency of specific polymorphisms of genes of the RAAS in premenopausal hypertensive women as compare to hypertensive postmenopausal women and men, 2) test the hypothesis that the administration of estradiol to postmenopausal hypertensive women with these specific polymorphisms in RAAS genes will alter the intermediate phenotype and lower blood pressure, 3) examine activity of the tissue RAAS according to specific genotypes in these three groups.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067332-02
Application #
6537996
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Program Officer
Lin, Michael
Project Start
2001-06-25
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$259,125
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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Ricchiuti, Vincent; Lapointe, Nathalie; Pojoga, Luminita et al. (2011) Dietary sodium intake regulates angiotensin II type 1, mineralocorticoid receptor, and associated signaling proteins in heart. J Endocrinol 211:47-54
Ricchiuti, Vincent; Lian, Christine G; Oestreicher, Eveline M et al. (2009) Estradiol increases angiotensin II type 1 receptor in hearts of ovariectomized rats. J Endocrinol 200:75-84
Ahmed, Sofia B; Bentley-Lewis, Rhonda; Hollenberg, Norman K et al. (2009) A comparison of prediction equations for estimating glomerular filtration rate in pregnancy. Hypertens Pregnancy 28:243-55
Mirza, Faryal S; Ong, Paul; Collins, Peter et al. (2008) Effects of estradiol and the angiotensin II receptor blocker irbesartan on vascular function in postmenopausal women. Menopause 15:44-50
Szmuilowicz, Emily D; Adler, Gail K; Ricchiuti, Vincent et al. (2007) Relationships between endogenous sex hormone concentrations and vascular function in postmenopausal women. J Clin Endocrinol Metab 92:4738-41
Szmuilowicz, Emily D; Adler, Gail K; Williams, Jonathan S et al. (2006) Relationship between aldosterone and progesterone in the human menstrual cycle. J Clin Endocrinol Metab 91:3981-7
Ounis-Skali, Nadia; Mitchell, Gary F; Solomon, Caren G et al. (2006) Changes in central arterial pressure waveforms during the normal menstrual cycle. J Investig Med 54:321-6
Heitritter, Shannon M; Solomon, Caren G; Mitchell, Gary F et al. (2005) Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab 90:3983-8
Bentley-Lewis, Rhonda; Graves, Steven W; Seely, Ellen W (2005) The renin-aldosterone response to stimulation and suppression during normal pregnancy. Hypertens Pregnancy 24:1-16

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