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- Fliegner, D, et al.
(author)
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Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload
- 2010
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In: American journal of physiology. Regulatory, integrative and comparative physiology. - : American Physiological Society. - 1522-1490 .- 0363-6119. ; 298:6, s. R1597-R1606
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Journal article (peer-reviewed)abstract
- We investigated sex differences and the role of estrogen receptor-β (ERβ) on myocardial hypertrophy in a mouse model of pressure overload. We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ERβ knockout (ERβ−/−) mice. All mice were characterized by echocardiography and hemodynamic measurements and were killed 9 wk after surgery. Left ventricular (LV) samples were analyzed by microarray profiling, real-time RT-PCR, and histology. After 9 wk, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. ERβ deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that WT male hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than WT female hearts. ERβ−/− mice exhibited a different transcriptional response. ERβ−/−/TAC mice of both sexes exhibited induction of proapoptotic genes with a stronger expression in ERβ−/− males. Cardiac fibrosis was more pronounced in male WT/TAC than in female mice. This difference was abolished in ERβ−/− mice. The number of apoptotic nuclei was increased in both sexes of ERβ−/−/TAC mice, most prominent in males. Female sex offers protection against ventricular chamber dilation in the TAC model. Both female sex and ERβ attenuate the development of fibrosis and apoptosis, thus slowing the progression to heart failure.
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| 2. |
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| 3. |
- Kararigas, G, et al.
(author)
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Role of the estrogen/estrogen-receptor-beta axis in the genomic response to pressure overload-induced hypertrophy
- 2011
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In: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 43:8, s. 438-446
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Journal article (peer-reviewed)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.
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