Endothelin-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice.
AIMS
The nitric oxide and endothelin systems are key components of a local paracrine hormone network in the heart. We previously reported that diastolic dysfunction observed in mice lacking the endothelial nitric oxide synthase (eNOS-/-) can be prevented by a genetic overexpression of ET-1. Sexual dimorphisms have been reported in both ET-1 and NO systems. Particularly, eNOS-/- mice present sex related phenotypic differences.


MAIN METHODS
We used the ET-1 transgenic (ET+/+), eNOS-/-, and crossbred ET+/+eNOS-/- mice, and wild type controls. We measured cardiac function by heart catheterization. Cardiac ventricles were collected for histological and molecular profiling.


KEY FINDINGS
We report here that (i) the level of ET-1 expression in eNOS-/- mice was elevated in males but not in females. (ii) Left ventricular end-diastolic blood pressure was higher in male eNOS-/- mice than in females. (ii) eNOS-/- males but not females developed cardiomyocyte hypertrophy. (iv) Perivascular fibrosis of intracardiac arteries developed in female ET+/+ and eNOS-/- mice but not in males. Additionally, (v) the cardiac expression of metalloprotease-9 was higher in eNOS-/- males compared to females. Finally, (vi) cardiac proteome analysis revealed that the protein abundance of the oxidative stress related enzyme superoxide dismutase presented with sexual dimorphism in eNOS-/- and ET+/+ mice.


SIGNIFICANCE
These results indicate that the cardiac phenotypes of ET-1 transgenic mice and eNOS knockout mice are sex specific. Since both systems are key players in the pathogenesis of cardiovascular diseases, our findings might be important in the context of gender differences in patients with such diseases.
['Vignon-Zellweger|Nicolas|N|', 'Relle|Katharina|K|', 'Rahnenführer|Jan|J|', 'Schwab|Karima|K|', 'Hocher|Berthold|B|', 'Theuring|Franz|F|']
D000818:Animals D001794:Blood Pressure D003094:Collagen D019332:Endothelin-1 D005260:Female D005355:Fibrosis D005786:Gene Expression Regulation D006334:Heart Function Tests D008297:Male D045726:Metalloproteases D018345:Mice, Knockout D009206:Myocardium D032383:Myocytes, Cardiac D052250:Nitric Oxide Synthase Type III D012333:RNA, Messenger D012727:Sex Characteristics D013599:Systole
Endothelin-1 Nitric oxide Sexual dimorphism Cardiac function