Role of the estrogen/estrogen-receptor-beta axis in the genomic response to pressure overload-induced hypertrophy

Abstract

Cardiac hypertrophy, the adaptive response of the heart to overload, is a major risk factor for heart failure and sudden death. Estrogen (E2) and estrogen receptor beta (ERbeta) offer protection against hypertrophy and in the transition to heart failure. However, the underlying pathways remain incompletely defined. We employed a publicly available microarray dataset of female wild-type (WT) and ERbeta knockout (BERKO) mice subjected to pressure overload-induced hypertrophy to perform a systematic investigation of the mechanisms involved in the protection conferred by the E2/ERbeta axis. We show that considerably more genes were modulated in response to pressure overload in BERKO mice than in WT mice. The majority of the identified candidates in BERKO mice were induced, while those in WT mice were repressed. Pathway analysis revealed a similar pattern. This study is the first to demonstrate that the lack of ERbeta led to a significant increase of inflammatory pathways. Mitochondrial bioenergetics- and oxidative stress-related pathways were also modulated. In conclusion, ERbeta acquires the role of gatekeeper of the genomic response of the heart to pressure overload-induced hypertrophy. This may offer the molecular explanation for its cardioprotective role. We consider the present study to be a useful resource and that it will contribute to downstream functional analysis and to the characterization of pathways with previously unknown role in hypertrophy.

Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones

“…Studies in various models of acute or chronic LV injury (including chronic LV pressure overload) demonstrated antifibrotic, antihypertrophic, anti-inflammatory, antiapoptotic/prosurvival, and antioxidant effects of E2, as well as beneficial effects on mitochondrial function (11,21,28,39,42,59). Furthermore, E2 enhances nitric oxide signaling in the LV (40), and a recent study suggested that LV inotropic effects of phosphodiesterase (PDE)-5 inhibition in female rodents are estrogen-dependent (48).…”

Transcriptome Characterization of Estrogen-Treated Human Myocardium Identifies Myosin Regulatory Light Chain Interacting Protein as a Sex-Specific Element Influencing Contractile Function

“…Microarray data analysis. Data were analyzed as described recently (10,11) and as summarized in the Online Methods. Mouse experiments.…”

Inherited Cardiomyopathies: From Genotype to Phenotype

“…Selective ERα agonism attenuates cardiac hypertrophy, increasing cardiac output, left ventricular stroke volume, and cardiac α-MyHC expression [96][97][98]. Signaling through ERβ has been studied in more depth and has been shown to counteract the development of cardiac hypertrophy by reducing the expression of hypertrophic markers, attenuating fibrosis, apoptosis and inflammation [99][100][101]. ERβ regulates a network of miRNAs, modulates p38 and ERK signaling, and affects calcineurin expression [102,103].…”