title: Endothelin-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Cardiovascular Research, Department of Pharmacology, Charité, Berlin, Germany. Electronic address: nvz@kobepharma-u.ac.jp.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignon-Zellweger
authors.affiliation: Center for Cardiovascular Research, Department of Pharmacology, Charité, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Relle
authors.affiliation: Center for Cardiovascular Research, Department of Pharmacology, Charité, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rahnenführer
authors.affiliation: Center for Cardiovascular Research, Department of Pharmacology, Charité, Berlin, Germany.
authors.forename: Karima
authors.initials: K
authors.lastname: Schwab
authors.affiliation: Nutritional Science, University of Potsdam, Potsdam, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
authors.affiliation: Center for Cardiovascular Research, Department of Pharmacology, Charité, Berlin, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Theuring
mesh_terms: D000818:Animals; D001794:Blood Pressure; D003094:Collagen / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D006334:Heart Function Tests; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D013599:Systole
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D003094:Collagen; D052250:Nitric Oxide Synthase Type III; D045726:Metalloproteases
keywords: Cardiac function; Endothelin-1; Nitric oxide; Sexual dimorphism