Heart failure in aging women differs from that in aging men, with more frequent diastolic dysfunction due to increased cardiac stiffness, for which there is no specific treatment. Premenopausal women appear to be protected from diastolic dysfunction, with a rapid increase in its incidence after menopause. Clinical evidence strongly suggests that the interaction between estrogen loss and activation of the cardiac renin-angiotensin-aldosterone system (RAAS) contributes to the development of hypertension and left ventricular (LV) hypertrophy in postmenopausal women, two risk factors for diastolic dysfunction. We have found that early estrogen depletion in the female mRen2 Lewis rat, a novel congenic strain, triggers the development of diastolic dysfunction, manifested by a pseudonormal Doppler pattern and increase in E/e'(reflective of high filling pressures);this is associated with increased cardiac collagen and serum aldosterone. These data lead to the overall hypothesis that loss of estrogen regulates two key enzymatic pathways within the cardiac RAAS to enhance ACE and suppress ACE2. The imbalance in these two enzymes ultimately results in sustained expression of angiotensin II and aldosterone, and a corresponding reduction in angiotensin-(1-7), promoting LV remodeling and diastolic stiffness. Using a reverse translational approach in ovariectomized versus estrogen-intact mRen2 rats, we will determine whether: 1) a shift from the antifibrotic to profibrotic limb of the cardiac RAAS contributes to LV remodeling and diastolic dysfunction following estrogen loss;2) estrogen replacement attenuates diastolic dysfunction by shifting the balance of the RAAS to ACE2 and angiotensin-(1-7);and 3) ACE2 inhibition attenuates the cardioprotective benefits of estrogen. The results from this study will be important because diastolic dysfunction is highly prevalent among postmenopausal women, yet the mechanisms and therefore optimal therapy are not well defined.

Public Health Relevance

Diastolic dysfunction contributes significantly to age-related heart failure, a major problem among elderly women. The overall goal of this proposal is to delineate the role of estrogen in the modulation of the cardiac renin-angiotensin-aldosterone system as it leads to cardiac remodeling and diastolic dysfunction using an established rodent model of hypertension and surgical menopause. Our results will help clarify optimal treatment of diastolic heart disease in postmenopausal women.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033727-04
Application #
8288151
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kohanski, Ronald A
Project Start
2009-07-15
Project End
2013-08-31
Budget Start
2012-07-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$288,712
Indirect Cost
$93,636
Name
Wake Forest University Health Sciences
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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Ahmad, Sarfaraz; Sun, Xuming; Lin, Marina et al. (2018) Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR. J Cell Physiol 233:3330-3342
Kim, Sunghye; Miller, Michael E; Lin, Marina et al. (2018) Self- vs proxy-reported mobility using the mobility assessment tool-short form in elderly preoperative patients. Eur Rev Aging Phys Act 15:5
da Silva, Jacqueline S; Gabriel-Costa, Daniele; Wang, Hao et al. (2017) Blunting of cardioprotective actions of estrogen in female rodent heart linked to altered expression of cardiac tissue chymase and ACE2. J Renin Angiotensin Aldosterone Syst 18:1470320317722270
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Alencar, Allan K; Montes, Guilherme C; Montagnoli, Tadeu et al. (2017) Activation of GPER ameliorates experimental pulmonary hypertension in male rats. Eur J Pharm Sci 97:208-217
Alencar, Allan K; da Silva, Jaqueline S; Lin, Marina et al. (2017) Effect of Age, Estrogen Status, and Late-Life GPER Activation on Cardiac Structure and Function in the Fischer344×Brown Norway Female Rat. J Gerontol A Biol Sci Med Sci 72:152-162
Wang, Hao; Sun, Xuming; Chou, Jeff et al. (2017) Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis. Biochim Biophys Acta Mol Basis Dis 1863:1870-1882
Wang, Hao; Alencar, Allan; Lin, Marina et al. (2016) Activation of GPR30 improves exercise capacity and skeletal muscle strength in senescent female Fischer344 × Brown Norway rats. Biochem Biophys Res Commun 475:81-6
Wang, Hao; da Silva, Jaqueline; Alencar, Allan et al. (2016) Mast Cell Inhibition Attenuates Cardiac Remodeling and Diastolic Dysfunction in Middle-aged, Ovariectomized Fischer 344 × Brown Norway Rats. J Cardiovasc Pharmacol 68:49-57

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