Interplay Between Estrogen, GPR30 and Chymase/RAS in Diastolic Function
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.