Estrogen Attenuates Left Ventricular and Cardiomyocyte Hypertrophy by an Estrogen Receptor–Dependent Pathway That Increases Calcineurin Degradation

Abstract

Left ventricular (LV) hypertrophy commonly develops in response to chronic hypertension and is a significant risk factor for heart failure and death. The serine-threonine phosphatase, calcineurin (CnA), plays a critical role in the development of pathologic hypertrophy. Previous experimental studies in murine models show that estrogen limits pressure overload-induced hypertrophy; our purpose was to explore further the mechanisms underlying this estrogen effect. Wild type, ovariectomized female mice were treated with placebo or 17β-estradiol (E2), followed by transverse aortic constriction (TAC) to induce pressure overload. At two weeks, mice underwent physiologic evaluation, immediate tissue harvest, or dispersion of cardiomyocytes. E2 replacement limited TAC-induced LV and cardiomyocyte hypertrophy while attenuating deterioration in LV systolic function and contractility. These E2 effects were associated with reduced abundance of CnA. The primary downstream targets of CnA are the nuclear factor of activated T-cell (NFAT) family of transcription factors. In transgenic mice expressing a NFAT-activated promoter-luciferase reporter gene, E2 limited TAC-induced activation of NFAT. Moreover, the inhibitory effects of E2 on LV hypertrophy were absent in CnA knockout mice supporting that CnA is an important target of E2-mediated inhibition. In cultured rat cardiac myocytes, E2 inhibited agonist-induced hypertrophy while also decreasing CnA abundance and NFAT activation. Agonist stimulation also reduced CnA ubiquitination and degradation that was prevented by E2; all in vitro effects of estrogen were reversed by an ER antagonist. These data support that E2 reduces pressure overload induced hypertrophy by an ER-dependent mechanism that increases CnA degradation, unveiling a novel mechanism by which E2 and ERs regulate pathologic LV and cardiomyocyte growth.

Tropomyosin Dephosphorylation Results in Compensated Cardiac Hypertrophy

“…Female TG mice show no changes when compared with female or male NTG hearts. Differences in the development of cardiac hypertrophy between sexes have been previously noted (20,32). Thus, the increase in cardiomyocyte area and left ventricular hypertrophy with no change in heart weight to body weight ratio or female cardiac enlargement demonstrates the moderate nature of this hypertrophic phenotype.…”

“…These TG hearts show no changes in functional parameters when investigated by echocardiography, myofilament Ca 2ϩ -tension relations, or in studies of work-performing heart during ␤-adrenergic stimulus. However, these animals do have sex-specific differences in heart morphology likely due to the cardioprotective effects of estrogen that have been described previously (19,20). Male TG mice show a hypertrophic phenotype as measured by echocardiography and supported by cardiomyocyte cross-sectional area measurements, whereas female mice do not.…”

Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice

“…8,32,36 Estrogen increases protein S-nitrosylation, a common posttranslational protein modification, 37 and reduces inflammatory markers 32,38 and afterload-or agonist-induced cardiac hypertrophy via the inhibition of calcineurin hypertrophic transcription factor and mitogen-activated protein kinase signaling pathways. 39 Estrogen also improves endothelial and myocardial function after ischemia by an antiapoptotic and pro-survival effect on cardiomyocytes, 40,41 endothelial progenitor cell mobilization 42 and mesenchymal stem cell-mediated vascular endothelial growth factor release. 43,44 These rapid effects of estrogen on the action of CF6 were not examined in this study.…”

Impact of Sex on the Prognostic Value of High-Sensitivity Cardiac Troponin I in the General Population: The HUNT Study

“…However, men also have higher blood pressure at a given age than women (1 ), as well as higher sympathetic nervous system activity (28 ). In addition, sex steroid hormones such as estrogen may attenuate cardiomyocyte and left ventricular hypertrophy (29 ). Accordingly, premenopausal women will commonly have low cardiac mass and hearts without subtle pathologic structural changes.…”