Estrogen Inhibits Mast Cell Chymase Release to Prevent Pressure Overload-Induced Adverse Cardiac Remodeling

Abstract

Estrogen regulation of myocardial chymase and chymase effects on cardiac remodeling are unknown. To test the hypothesis that estrogen prevents pressure overload-induced adverse cardiac remodeling by inhibiting mast cell chymase release, transverse aortic constriction or sham surgery was performed in 7-week-old intact and ovariectomized rats. Three days prior to creating the constriction, additional groups of ovariectomized rats began receiving 17β-Estradiol, a chymase inhibitor, or a mast cell stabilizer. Left ventricular function, cardiomyocyte size, collagen volume fraction, mast cell density and degranulation, and myocardial and plasma chymase levels were assessed 18 days post-surgery. Aortic constriction resulted in ventricular hypertrophy in intact and ovariectomized groups while collagen volume fraction was increased only in ovariectomized rats. Chymase protein content was increased by aortic constriction in the intact and ovariectomized groups with the magnitude of the increase being greater in ovariectomized rats. Mast cell density and degranulation, plasma chymase levels and myocardial active transforming growth factor- 1 levels were increased by aortic constriction only in ovariectomized rats. Estrogen replacement markedly attenuated the constriction-increased myocardial chymase, mast cell density and degranulation, plasma chymase and myocardial active transforming growth factor- 1 as well as prevented ventricular hypertrophy and increased collagen volume fraction. Chymostatin attenuated the aortic constriction induced ventricular hypertrophy and collagen volume fraction in the ovariectomized rats similar to that achieved by estrogen replacement. Nedocromil yielded similar effects except for the reduction of chymase content. We conclude that the estrogen-inhibited release of mast cell chymase is responsible for the cardioprotection against transverse aortic constriction-induced adverse cardiac remodeling.

Estrogens and Myocardial Chymase

“…In addition, by inhibiting chymase with chymostatin or by using the mast cell stabilizer nedocromil, similar findings were observed. 2 These observations underscore the role of the estrogen-chymase-angiotensin II-pathological LVH path and add new insights into the mechanisms, prevention, and possibly treatment of HFpEF (and possibly of other myocardial diseases), particularly in postmenopausal women.…”

“…10 Recent insights from models that mimic the cardiac phenotype of an estrogeninsufficient/deficient woman (eg, premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2. Lewis female rat, as well as the current model, 2 provide evidence showing that estrogen modulates the tissue renin-angiotensin--aldosterone system and nitric oxide synthase system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 also called G protein-coupled estrogen receptor 1, 10 which might also be related to the pro remodeling Rho A/Rho kinase signaling pathway.…”

“…However, plasma chymase levels were increased by transverse aortic constriction only in ovariectomized rats. 2 Little or no progress has been made in identifying evidencebased, effective treatments, and no medical therapy to date does improve survival in patients with HFpEF, 6 including β-blockers, renin-angiotensin system antagonists, aldosterone antagonists, and phosphodiesterase-5 inhibitors. Thus, treatment of HFpEF remains largely empirical, and almost no acknowledged standards exist.…”

“…In response to pressure overload, they observed that ovarectomy induced higher levels of LVH. 2 Prevalence of HFpEF is 1.5% to 4.8%, 3 it is increasing and women seem to outnumber men by a 2:1 ratio. 4 In the recent trial of preserved cardiac function heart failure (HF) with the aldosterone antagonist spironolactone (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]), mean age was 68.6 years, 91% had hypertension, and 52% of the patients were women.…”

“…In this issue of Hypertension, in an experimental model of pressure overload induced heart disease in ovariectomyzed rats (as an equivalent to postmenopausal women), Li et al 2 found left ventricular hypertrophy (LVH), normal systolic function, and increased myocardial collagen. Their model is rather similar to heart failure with preserved ejection fraction (HFpEF), commonly because of diastolic dysfuncion induced by hypertensive heart disease.…”