The coronary heart disease (CHD) of postmenopausal women likely begins premenopausally and is exacerbated by estrogen deficiency. Thus, soy protein isolate with isoflavones (SOY), which is often consumed postmenopausally as a """"""""heart healthy"""""""" supplement, may also offer premenopausal cardiovascular benefit. Yet, the optimal timing for intervention (in relation to menopausal status and lesion stage) remains uncertain, as does the extent of cardiovascular protection provided to women first exposed to SOY as adults. Premenopausal monkeys (Macaca fascicu/aris) are a surrogate for reproductive aged women in the study of atherosclerosis and CHD risk. In this model, the stress of social subordination (low status) induces estrogen deficiency, accelerates atherogenesis, and impairs vascular responsivity. Treatment of low status premenopausal females with exogenous estrogen reduces the extent of postmenopausal atherosclerosis independent of postmenopausal hormone exposure, demonstrating the potential benefit of premenopausal prevention. It is therefore proposed to expand the scope of an ongoing study that currently contains sociallyhoused, premenopausal monkeys consuming a moderately atherogenic diet, in which protein is derived from either SOY or casein-lactalbumin (C/L). This study was designed initially to determine whether SOY inhibits premenopausal coronary atherosclerosis in stressed individuals and whether such effects are influenced by endogenous estrogen. This design does not permit determination of the relative postmenopausal cardiovascular effects of pre- vs. postmenopausal SOY exposure, a comparison that could directly inform the treatment of postmenopausal women. The present application proposes to answer the odginai premenopausal study question by assessing atherosclerosis in an lilac artery biopsy (a validated coronary artery surrogate), eliminating the need to necropsy the premenopausal animals. Instead, the study will be extended to include a surgically postmenopausal phase which, by switching the protein source for half of the monkeys, will cross pre- and postmenopausal exposure to C/L and SOY in a 2 x 2 factorial design encompassing 4 treatment conditions (SOY ? SOY, SOY ? C/L, C/L ? SOY, and C/L ? C/L). The study will terminate with the evaluation of lilac, coronary, and carotid artery atherosclerosis.
The aims are to test the hypothesis that the timing of SOY supplementation (pre- or postmenopausal) affects postmenopausal plaque progression and complications, and to determine the impact of chronic SOY exposure on noncardiovascutar, health-related outcomes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079421-03
Application #
7176933
Study Section
Special Emphasis Panel (ZRG1-ASG (01))
Program Officer
Rabadan-Diehl, Cristina
Project Start
2005-01-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$663,079
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Meléndez, Giselle C; Register, Thomas C; Appt, Susan E et al. (2015) Beneficial effects of soy supplementation on postmenopausal atherosclerosis are dependent on pretreatment stage of plaque progression. Menopause 22:289-96
Silverstein, Marnie G; Kaplan, Jay R; Appt, Susan E et al. (2014) Effect of soy isoflavones on thyroid hormones in intact and ovariectomized cynomolgus monkeys (Macaca fascicularis). Menopause 21:1136-42
Ethun, K F; Wood, C E; Parker Jr, C R et al. (2012) Effect of ovarian aging on androgen biosynthesis in a cynomolgus macaque model. Climacteric 15:82-92
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Schnatz, Peter F; Vila-Wright, Sharon; Jiang, Xuezhi et al. (2012) The association between plasma 25-hydroxyvitamin D3 concentrations, C-reactive protein levels, and coronary artery atherosclerosis in postmenopausal monkeys. Menopause 19:1074-80
Schnatz, Peter F; Nudy, Matthew; O'Sullivan, David M et al. (2012) Coronary artery vitamin D receptor expression and plasma concentrations of 25-hydroxyvitamin D: their association with atherosclerosis. Menopause 19:967-73
Hamilton, Ryan T; Rettberg, Jamaica R; Mao, Zisu et al. (2011) Hippocampal responsiveness to 17ýý-estradiol and equol after long-term ovariectomy: implication for a therapeutic window of opportunity. Brain Res 1379:11-22
Rettberg, Jamaica R; Hamilton, Ryan T; Mao, Zisu et al. (2011) The effect of dietary soy isoflavones before and after ovariectomy on hippocampal protein markers of mitochondrial bioenergetics and antioxidant activity in female monkeys. Brain Res 1379:23-33
Appt, Susan E; Chen, Haiying; Goode, Amanda K et al. (2010) The effect of diet and cardiovascular risk on ovarian aging in cynomolgus monkeys (Macaca fascicularis). Menopause 17:741-8
Appt, Susan E; Ethun, Kelly F (2010) Reproductive aging and risk for chronic disease: Insights from studies of nonhuman primates. Maturitas 67:7-14

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