Sex-specific modification of progesterone receptor expression by 17β-oestradiol in human cardiac tissues

Abstract

BackgroundAlthough circulating levels of sexual hormones in elderly men and women are low and quite similar, the adaptation of the elderly heart to stress differs between the sexes. We have hypothesized that the effects of sexual hormones in the heart may differ in men and women. Here, we assessed whether 17β-oestradiol regulates gene expression in the human heart in a sex-dependent manner. We selected the progesterone receptor as a well studied 17β-oestradiol target that may be pathologically linked to cardiac remodelling.MethodsIn order to assess the ex vivo effects of 17β-oestradiol in intact human cardiac tissues, we developed a 24-h model for the culture of human atrial myocardium. We verified tissue viability after 24 h in culture with two standard assays to determine the degree of apoptosis and metabolic activity of cardiac tissues. Progesterone receptor mRNA and protein level were measured after 24-h treatment of tissues with 17β-oestradiol. Statistical analysis was performed by the Mann-Whitney U test and two-way ANOVA.ResultsWe established a tissue culture model that allows for the study of viable human cardiac tissue over a 24-h period. After 24 h, cultured cardiac tissues revealed low apoptosis, retained their metabolic activity and, therefore, remained viable. Treatment with 17β-oestradiol led to an induction of the progesterone receptor mRNA level in female (P = 0.001) but not in male tissues. Similarly, there was an increase in the level of progesterone receptor protein in female tissues (P = 0.03), while a decreasing trend was observed in male tissues (P = 0.079) exposed to 17β-oestradiol.ConclusionsOur novel finding may offer a molecular explanation for the sex-specific differences observed in cardiac remodelling. The culture model we established for human cardiac tissue will facilitate the study of cellular processes in health and disease and will be of use for pharmacological testing.

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

“…This finding further suggested that the sex might play an important role in the regulation of gene expression by E2. Divergent hormonal effects on gene expression in male and Mylip Expression Levels in E2-Treated Mouse CMs female mice were suggested earlier (23), a finding that we recently confirmed in the human heart for progesterone receptor (9). We now demonstrate that E2 regulates gene expression in a sex-specific manner, particularly in CMs.…”

“…Small quantitative differences in the amount of RNA might have relevant qualitative effects at a functional level. To this extent, we recently suggested that the heart is a highly regulated environment, where minor changes may have major effects (9). Here, we provide evidence supporting this notion.…”

“…Tissue harvest, culture, and treatment were recently described (9) and are summarized in the Online Methods. Tissues from 6 patients (50% women) undergoing coronary bypass surgery were treated with 10 Ϫ8 mol/l E2 or 2-hydroxypropyl-␤-cyclodextrin (HBC) (vehicle control for E2 treatment) for 24 h. This concentration was chosen to obtain an E2 level of physiological range.…”

“…Quantitative real-time reverse transcription PCR. Reactions were performed as described previously (9) and as summarized in the Online Methods. Immunoblotting and coimmunoprecipitation.…”

On Male-Specific Estrogen Action

“…In human macrophages, estrogen-and progesterone-mediated inhibition of cholesterol esterification and, by extension, foam cell formation, occurs only in female-derived macrophages (4). Conversely, androgens enhance cholesterol esterification only in male-derived macrophages (4). However, in the current report on Mylip regulation, we have the first seemingly counterintuitive example of a male-specific gene response to estrogen.…”