Hypertension and left ventricular diastolic dysfunction (LVDD) precede heart failure (HF) in women, particularly with the loss of ovarian estrogens (e.g., with menopause or premature ovarian failure). There are no proven pharmacologic interventions that delay or reverse LVDD or subsequent diastolic HF. The renin- angiotensin system (RAS) plays a key role in the pathophysiology of hypertensive heart disease, but trials suggest ACE inhibitors may be less effective in women than men receiving treatment for hypertension and HF. The discovery that chymase can form Ang II directly from Ang-(1-12), independent of ACE, has opened up a new direction in research on the pathogenesis of LVDD in women. We showed that chronic activation of the novel estrogen receptor GPR30 by its agonist G1 mitigated the adverse effects of estrogen loss on the cardiac LVDD phenotype and reduced expression of cardiac chymase, suggesting a mechanistic link between GPR30 and the local RAS. Our long-term goal is to understand how changes in chymase/RAS metabolism after estrogen loss triggers maladaptive pathways leading to fibrosis and LVDD. The objective of this project is to determine the mechanism by which E2/GPR30 limits the action of mast cell chymase on intracellular Ang II formation from Ang-(1-12) in cardiomyocytes. We hypothesize that expression and function of chymase and Ang-(1-12) are higher in the hearts of hypertensive animals with disrupted estrogen activity, and that these effects can be reversed with estrogen (E2) replacement and GPR30 activation. Guided by strong preliminary data, we will test our hypothesis in three aims: 1) Characterize the autocrine/paracrine enzymatic pathway leading to cardiac Ang II formation, LVDD, and remodeling after estrogen loss; 2) Determine if E2 activation of GPR30, as opposed to activation of the classic estrogen receptors ER and ER, limits cardiac chymase/Ang-(1-12) metabolism to preserve LV structure and function; and 3) Identify E2/GPR30-specific mechanisms that negatively regulate chymase production/release from mast cells and chymase-mediated Ang-(1-12) metabolism/Ang II production in cardiomyocytes. Our innovative global systems biology approach integrates the use of (a) physiological, biochemical, cellular, and molecular methodologies; (b) transgenic rodent and murine models; (c) cultured mast cells and cardiomyocytes; and (d) GPR30-, ER-, and ER-gene silenced cells in vitro. Confirmation of our hypothesis will significantly advance our understanding of how mast cell chymase, Ang-(1-12), and Ang II expression and function may be regulated by E2 via GPR30, and provide a mechanism that explains why RAS inhibitors are less effective in blocking Ang II-mediated adverse cardiac remodeling and LVDD in women after estrogen loss.
Hypertension and left ventricular diastolic dysfunction (LVDD) are seen more often in women with estrogen (E2) insufficiency or deficiency due to premature ovarian failure or menopause. Women develop diastolic heart failure (HF) twice as often as men; however, uncertainty regarding the action of estrogens on the heart persists and little is known about the influence of estrogens on the metabolism of the cardiac renin angiotensin system (RAS). The proposed research will unravel 1) the link between E2 loss and the pathways for intracellular and interstitial Ang II formation from Ang-1-(1-12) by chymase that contribute to LVDD, and 2) provide an explanation for the limited effectiveness of RAS-directed therapies in women with HF.
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