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Moderate inappropriately high aldosterone/NaCl constellation in mice: cardiovascular effects and the role of cardiovascular epidermal growth factor receptor.

Schreier B, Rabe S, Winter S, Ruhs S, Mildenberger S, Schneider B, Sibilia M, Gotthardt M, Kempe S, Mäder K, Grossmann C, Gekle M - Sci Rep (2014)

Bottom Line: Non-physiological activation of the mineralocorticoid receptor (MR), e.g. by aldosterone under conditions of high salt intake, contributes to the pathogenesis of cardiovascular diseases, although beneficial effects of aldosterone also have been described.Therefore we performed an experimental series in male and female animals each, using a recently established mouse model with EGFR knockout in vascular smooth muscle cells and cardiomyocytes and determined the effects of a mild-high aldosterone-to-NaCl constellation on a.o. marker gene expression, heart size, systolic blood pressure, impulse conduction and heart rate.Our data show that (i) cardiac tissue of male but not of female mice is sensitive to mild aldosterone/NaCl treatment, (ii) EGFR knockout induces stronger cardiac disturbances in male as compared to female animals and (iii) mild aldosterone/NaCl treatment requires the EGFR in order to disturb cardiac tissue homeostasis whereas beneficial effects of aldosterone seem to be independent of EGFR.

View Article: PubMed Central - PubMed

Affiliation: Julius-Bernstein-Institute of Physiology, Medical Faculty, University of Halle-Wittenberg, Halle, Germany.

ABSTRACT
Non-physiological activation of the mineralocorticoid receptor (MR), e.g. by aldosterone under conditions of high salt intake, contributes to the pathogenesis of cardiovascular diseases, although beneficial effects of aldosterone also have been described. The epidermal growth factor receptor (EGFR) contributes to cardiovascular alterations and mediates part of the MR effects. Recently, we showed that EGFR is required for physiological homeostasis and function of heart and arteries in adult animals. We hypothesize that moderate high aldosterone/NaCl, at normal blood pressure, affects the cardiovascular system depending on cardiovascular EGFR. Therefore we performed an experimental series in male and female animals each, using a recently established mouse model with EGFR knockout in vascular smooth muscle cells and cardiomyocytes and determined the effects of a mild-high aldosterone-to-NaCl constellation on a.o. marker gene expression, heart size, systolic blood pressure, impulse conduction and heart rate. Our data show that (i) cardiac tissue of male but not of female mice is sensitive to mild aldosterone/NaCl treatment, (ii) EGFR knockout induces stronger cardiac disturbances in male as compared to female animals and (iii) mild aldosterone/NaCl treatment requires the EGFR in order to disturb cardiac tissue homeostasis whereas beneficial effects of aldosterone seem to be independent of EGFR.

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Effect of genotype and treatment on organ weights in male and female animals.Wildtype and knockout animals were either untreated or treated with aldosterone/NaCl for 28 days. Afterwards the animals were sacrificed and the body weight (a, d), heart weight/tibia length (b, e) and lung weight/tibia length (c, f) were determined with respect to gender. Data are given as mean ± SEM, * p<0.05 compared to respective wildtype, # p<0.05 compared to respective control, N = 9–12 animals/group.
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f2: Effect of genotype and treatment on organ weights in male and female animals.Wildtype and knockout animals were either untreated or treated with aldosterone/NaCl for 28 days. Afterwards the animals were sacrificed and the body weight (a, d), heart weight/tibia length (b, e) and lung weight/tibia length (c, f) were determined with respect to gender. Data are given as mean ± SEM, * p<0.05 compared to respective wildtype, # p<0.05 compared to respective control, N = 9–12 animals/group.

Mentions: To rule out growth defects caused by the knockout of EGFR and as heart failure can lead to lung congestion organ weights were evaluated. There was no difference in body (Fig 2A and 2D) and lung weight (Fig 2C and 2F) for any of the four groups of both genders. As predicted from a previous study, heart weight was enhanced in knockout animals of the control groups (Fig 2B and 2E). In extension to previous studies, the data presented here show that the degree of cardiac hypertrophy is significantly higher in male knockout animals (306 ± 22% of WT for male KO animals; 218 ± 23% of WT for female KO animals, N = 8–10). In order to gain more insight into the time course of hypertrophy development we investigated heart size of newborn animals of either gender (N = 5 for each group). Heart weight per body weight was 5.73 ± 0.18 mg/g for male and 5.64 ± 0.16 mg/g for female wildtype animals. The values for knockout animals were 7.98 ± 0.26 mg/g (male) and 8.04 ± 0.52 mg/g (female). Thus, there is a similar (~35%) cardiac hypertrophy at birth in male and female knockout animals. After birth hypertrophy aggravates, yet to a greater extend in male animals as compared to females.


Moderate inappropriately high aldosterone/NaCl constellation in mice: cardiovascular effects and the role of cardiovascular epidermal growth factor receptor.

Schreier B, Rabe S, Winter S, Ruhs S, Mildenberger S, Schneider B, Sibilia M, Gotthardt M, Kempe S, Mäder K, Grossmann C, Gekle M - Sci Rep (2014)

Effect of genotype and treatment on organ weights in male and female animals.Wildtype and knockout animals were either untreated or treated with aldosterone/NaCl for 28 days. Afterwards the animals were sacrificed and the body weight (a, d), heart weight/tibia length (b, e) and lung weight/tibia length (c, f) were determined with respect to gender. Data are given as mean ± SEM, * p<0.05 compared to respective wildtype, # p<0.05 compared to respective control, N = 9–12 animals/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4262830&req=5

f2: Effect of genotype and treatment on organ weights in male and female animals.Wildtype and knockout animals were either untreated or treated with aldosterone/NaCl for 28 days. Afterwards the animals were sacrificed and the body weight (a, d), heart weight/tibia length (b, e) and lung weight/tibia length (c, f) were determined with respect to gender. Data are given as mean ± SEM, * p<0.05 compared to respective wildtype, # p<0.05 compared to respective control, N = 9–12 animals/group.
Mentions: To rule out growth defects caused by the knockout of EGFR and as heart failure can lead to lung congestion organ weights were evaluated. There was no difference in body (Fig 2A and 2D) and lung weight (Fig 2C and 2F) for any of the four groups of both genders. As predicted from a previous study, heart weight was enhanced in knockout animals of the control groups (Fig 2B and 2E). In extension to previous studies, the data presented here show that the degree of cardiac hypertrophy is significantly higher in male knockout animals (306 ± 22% of WT for male KO animals; 218 ± 23% of WT for female KO animals, N = 8–10). In order to gain more insight into the time course of hypertrophy development we investigated heart size of newborn animals of either gender (N = 5 for each group). Heart weight per body weight was 5.73 ± 0.18 mg/g for male and 5.64 ± 0.16 mg/g for female wildtype animals. The values for knockout animals were 7.98 ± 0.26 mg/g (male) and 8.04 ± 0.52 mg/g (female). Thus, there is a similar (~35%) cardiac hypertrophy at birth in male and female knockout animals. After birth hypertrophy aggravates, yet to a greater extend in male animals as compared to females.

Bottom Line: Non-physiological activation of the mineralocorticoid receptor (MR), e.g. by aldosterone under conditions of high salt intake, contributes to the pathogenesis of cardiovascular diseases, although beneficial effects of aldosterone also have been described.Therefore we performed an experimental series in male and female animals each, using a recently established mouse model with EGFR knockout in vascular smooth muscle cells and cardiomyocytes and determined the effects of a mild-high aldosterone-to-NaCl constellation on a.o. marker gene expression, heart size, systolic blood pressure, impulse conduction and heart rate.Our data show that (i) cardiac tissue of male but not of female mice is sensitive to mild aldosterone/NaCl treatment, (ii) EGFR knockout induces stronger cardiac disturbances in male as compared to female animals and (iii) mild aldosterone/NaCl treatment requires the EGFR in order to disturb cardiac tissue homeostasis whereas beneficial effects of aldosterone seem to be independent of EGFR.

View Article: PubMed Central - PubMed

Affiliation: Julius-Bernstein-Institute of Physiology, Medical Faculty, University of Halle-Wittenberg, Halle, Germany.

ABSTRACT
Non-physiological activation of the mineralocorticoid receptor (MR), e.g. by aldosterone under conditions of high salt intake, contributes to the pathogenesis of cardiovascular diseases, although beneficial effects of aldosterone also have been described. The epidermal growth factor receptor (EGFR) contributes to cardiovascular alterations and mediates part of the MR effects. Recently, we showed that EGFR is required for physiological homeostasis and function of heart and arteries in adult animals. We hypothesize that moderate high aldosterone/NaCl, at normal blood pressure, affects the cardiovascular system depending on cardiovascular EGFR. Therefore we performed an experimental series in male and female animals each, using a recently established mouse model with EGFR knockout in vascular smooth muscle cells and cardiomyocytes and determined the effects of a mild-high aldosterone-to-NaCl constellation on a.o. marker gene expression, heart size, systolic blood pressure, impulse conduction and heart rate. Our data show that (i) cardiac tissue of male but not of female mice is sensitive to mild aldosterone/NaCl treatment, (ii) EGFR knockout induces stronger cardiac disturbances in male as compared to female animals and (iii) mild aldosterone/NaCl treatment requires the EGFR in order to disturb cardiac tissue homeostasis whereas beneficial effects of aldosterone seem to be independent of EGFR.

Show MeSH
Related in: MedlinePlus