Female sex and estrogen receptor-β attenuate cardiac remodeling and apoptosis in pressure overload

Fliegner, Daniela; Schubert, Carola; Penkalla, Adam; Witt, Henning; Kararigas, Georgios; Dworatzek, Elke; Staub, Eike; Martus, Peter; Noppinger, Patricia Ruiz; Kintscher, Ulrich; Gustafsson, Jan‐Åke; Regitz‐Zagrosek, Vera

doi:10.1152/ajpregu.00825.2009

Cited by 209 publications

(183 citation statements)

References 46 publications

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“…Testosterone-induced ROS generation promotes migration of VSMCs, and this effect is increased in VSMCs of hypertensive rats (11), in agreement with the assumption that increased ROS levels play an important role in the pathophysiology of arterial hypertension (6,49). Also, in line with our results, cardiomyocyte death is markedly greater in men than in women (20) and O 2 Ϫ production and vascular remodeling are higher in injured femoral arteries of male mice (48). It is possible that these events are associated with greater testosterone levels in males and testosterone effects on ROS generation and apoptosis.…”

Section: Discussionsupporting

confidence: 90%

Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement

Lopes

Neves

Pestana

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Section: Discussionsupporting

confidence: 90%

Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement

Lopes

Neves

Pestana

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…24 Most studies have focused on the transverse aortic constriction model. 25 This model features an initial adaptive response to compensate for elevated ventricular pressures to normalize wall stress. In contrast, cardiac remodeling in the normotensive DOCA-salt model is induced by local and systemic actions of DOCA (mimicking aldosterone) and ET-1 on cardiomyocyte biological responses.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor-β Signals Left Ventricular Hypertrophy Sex Differences in Normotensive Deoxycorticosterone Acetate-Salt Mice

et al. 2011

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Abstract-We found earlier that deoxycorticosterone acetate-salt treatment causes blood pressure-independent left ventricular hypertrophy, but only in male mice. To test the hypothesis that the estrogen receptor-␤ (ER␤) protects the females from left ventricular hypertrophy, we treated male and female ER␤-deficient (ER␤ Ϫ/Ϫ ) mice and their male and female littermates (wild-type [WT]) with deoxycorticosterone acetate-salt and made them telemetrically normotensive with hydralazine. WT males had increased (ϩ16%) heart weight/tibia length ratios compared with WT females (ϩ7%) at 6 weeks. In ER␤ Ϫ/Ϫ mice, this situation was reversed. Female WT mice had the greatest heart weight/tibia length ratio increases of all of the groups (ϩ23%), even greater than ER␤ Ϫ/Ϫ males (ϩ10%). Echocardiography revealed concentric left ventricular hypertrophy in male WT mice, whereas ER␤ Ϫ/Ϫ females developed dilative left ventricular hypertrophy. The hypertrophic response in female ER␤ Ϫ/Ϫ mice was accompanied by the highest degree of collagen deposition, indicating maladaptive remodeling. ER␤ ϩ/ϩ females showed robust protective p38 and extracellular signal-regulated kinase 1/2 signaling relationships compared with other groups. Calcineurin A␤ expression and its positive regulator myocyte-enriched calcineurin-interacting protein 1 were increased in deoxycorticosterone acetate-salt female ER␤ Ϫ/Ϫ mice, yet lower than in WT males. Endothelin increased murine cardiomyocyte hypertrophy in vitro, which could be blocked by estradiol and an ER␤ agonist. We conclude that a functional ER␤ is essential for inducing adaptive p38 and extracellular signal-regulated kinase signaling, while reducing maladaptive calcineurin signaling in normotensive deoxycorticosterone acetate female mice. Our findings address the possibility of sex-specific cardiovascular therapies. Key Words: estrogen receptor-␤, heart Ⅲ hypertrophy Ⅲ fibrosis Ⅲ calcineurin Ⅲ p38 MAPK Ⅲ ERK1/2 F emales seem to be relatively protected from cardiovascular disease on the basis of animal and human studies; estrogens could play a role. 1-3 Clinical trials using estrogens for improving cardiovascular health were disappointing, perhaps because of poor estrogen receptor (ER) isoform selectivity and specificity. 4 The 2 functional isoforms, ER␣ and ER␤, are expressed in the myocardium. 5 Receptor-mediated effects of estrogens on cardiomyocyte biology are injury or stimulus dependent, 4,6 which, in turn, implicates activation of distinct, sex-dependent, signaling pathways and gene expression programs. 7 We described recently a sex-specific dimorphism in cardiac adaptation in response to deoxycorticosterone acetate (DOCA)-salt and showed that this response was independent of blood pressure. 8 Male mice developed left ventricular hypertrophy (LVH) that was linked to activation of a calcineurin-dependent pathway, which increased proinflammatory and profibrotic responses. In contrast, female DOCA mice maintained their initial physiological adaptive cardiac phenotype despite mineralocorticoid and...

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“…22 Cardiac fibrosis was more pronounced in male TAC than in female TAC mice. Female sex attenuated the development of fibrosis and apoptosis and offered protection against ventricular chamber dilation in the TAC model.…”

Section: Sex Differences In Hfmentioning

confidence: 94%

Sex and Gender Differences in Myocardial Hypertrophy and Heart Failure

Regitz‐Zagrosek

Oertelt‐Prigione

Seeland

et al. 2010

Circ J

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EpidemiologyHeart failure (HF) is one of the leading hospital discharge diagnoses in the modern world and has enormous implications with respect to cardiovascular mortality and morbidity, to individual quality of life experiences and societal resource utilization. The number of patients with HF is continuously increasing. Approximately 10% of 70-year-olds are affected, with an increasing prevalence after that age. HF patients have a life expectancy of approximately 5 years, similar to patients with malignant disease. Women with HF are older than their male counterparts and more likely to exhibit a non-ischemic cause of the disease. 1 The population-based Framingham study suggests that the prognosis in women is significantly better than in men after the onset of HF. 2 However, despite the higher mortality in men, given the overall longer lifespan of women, total numbers of HF deaths are higher in women. The incidence of HF increases dramatically in the female population over 55 years, further compensating the sex differences in mortality. This also appears to account for the stronger correlation between age and mortality observed in women. In fact, in men the NYHA class at baseline is the strongest predictor of mortality, whereas in women it is age. African-Americans might have a higher incidence of HF than Caucasians, with men affected more frequently than females.Major risk factors in both sexes are: age, presence of diabetes, anemia, elevated blood pressure, presence of AF, myocardial hypertrophy (MH) and prior myocardial infarction. Distribution of risk factors differs between the sexes. Women more frequently exhibit hypertension 1,3 and diabetes mellitus. 1,3 Hypertension contributes to the population attributable risk for HF in women to a greater extent than in men. 4 Obesity, diabetes, and impaired glucose carry a greater risk in women and inhibit or impair myocardial metabolism more severely in women than in men. 5-7 Men are more likely to suffer from preexisting coronary heart disease 1,8 and dilated cardiomyopathy (DCM). In the Euro HF survey, systolic HF was found predominantly in men whereas women presented with HF with preserved ejection fraction (EF) or diastolic HF. 9-11 Both systolic and diastolic HF carry a poor prognosis, with astonishingly small differences. 12 MH is a major risk factor for HF and is a negative prognostic sign in itself. Interestingly, women are better protected against the development of MH than men. However, even though MH appears later in women than it does in men at a given hemodynamic load, once established, it is more malign in women. 13 Left ventricular (LV) mass has been presented as the strongest independent mortality predictor in females. Sex and Gender Differences in Myocardial Hypertrophyand Heart Failure Vera Regitz-Zagrosek, MD; Sabine Oertelt-Prigione, MD; Ute Seeland, MD; Roland Hetzer, MDHeart failure (HF) is a leading cause of cardiovascular mortality and morbidity in the Western world. It affects men at younger age than women. Women have more frequently diast...

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Female sex and estrogen receptor-β attenuate cardiac remodeling and apoptosis in pressure overload

Cited by 209 publications

References 46 publications

Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement

Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement

Estrogen Receptor-β Signals Left Ventricular Hypertrophy Sex Differences in Normotensive Deoxycorticosterone Acetate-Salt Mice

Sex and Gender Differences in Myocardial Hypertrophy and Heart Failure

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