The higher prevalence of left ventricular diastolic dysfunction (LVDD) in postmenopausal women suggests a link with estrogen loss. Because LVDD may progress to diastolic heart failure after menopause, there is a significant need for therapies that confer the cardiovascular benefits of estrogen replacement therapy without its adverse effects. Our long-term goal is to better understand the role of a new estrogen receptor, GPR30, in the maintenance of cardiac structure and function in the female heart, and the mechanisms underlying cardiac remodeling and LVDD after estrogen loss and during aging. The objective of this application is to reveal the cardioprotective role of GPR30 signaling and interactions with the local renin-angiotensin system (RAS) and how this interaction affects the progression of LVDD in post-menopausal women. Specifically, we will determine the intracellular relationships between GPR30 and chymase-mediated angiotensin II (Ang II) formation and the maladaptive pathways that lead to fibrosis and lusitropic dysfunction, using estrogen-sensitive animal models of cardiac aging. Our central hypothesis is that GPR30 activation favorably regulates the structure and function of cardiofibroblasts and cardiomyocytes by inhibiting intracellular chymase/Ang II, thereby preserving the myocardial extracellular matrix, LV compliance, and diastolic function. Guided by strong preliminary data, we will test our hypothesis by pursuing three specific aims: 1) Characterize the inhibitory role of GPR30 on chymase-mediated Ang II expression and its adverse actions that lead to LV remodeling and LVDD during aging and estrogen loss in rats and mice; 2) Define the molecular mechanisms and roles of chymase/RAS deactivation in the attenuation of cardiac fibrosis by GPR30; and 3) Determine the intrinsic regulation of LV myocyte lusitropy and anti-hypertrophic remodeling by GPR30 and its interplay with intracellular chymase/RAS. To achieve these aims, we will use a global systems biology approach that integrates (a) physiological, cellular, and molecular methodologies; (b) rodent models of normal female cardiovascular aging and age-related cardiac GPR30 deactivation; and (c) cultured cardiofibroblasts and cardiomyocytes derived from the aging heart with or without GPR30 gene or chymase gene silencing. Our innovative approach will integrate information from both the organismal level (whole animal/whole heart) and the single-cell level to generate valuable translational data that more accurately describes GPR30/chymase/RAS pathway function in cardiac physiology and LVDD. The proposed research is significant because confirmation of our hypothesis will advance understanding of how estrogen protects the premenopausal heart from cardiac disease, and provide the impetus for future clinical studies focused on the efficacy of GPR30 activation and/or chymase inhibition in the prevention and treatment of LVDD, and its progression to heart failure, in aging women.

Public Health Relevance

Diastolic heart failure risk increases in women after menopause, suggesting a link between the loss of estrogen and diastolic dysfunction, it precursor. These studies will determine the role of a new G-coupled protein estrogen receptor, GPR30, on limiting chymase-mediated angiotensin II production and adverse effects in the female heart following estrogen deprivation and during aging. The proposed research will augment fundamental knowledge about the cause of female sex-specific diastolic dysfunction, leading to interventions that may halt its progression and improve quality of life among older women.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG033727-09
Application #
9302228
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kerr, Candace L
Project Start
2009-07-15
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2019-06-30
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost
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
Wang, Hao; Sun, Xuming; Chou, Jeff et al. (2017) Inflammatory and mitochondrial gene expression data in GPER-deficient cardiomyocytes from male and female mice. Data Brief 10:465-473
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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