title: Endothelin-1 overexpression restores diastolic function in eNOS knockout mice.
abstract: BACKGROUND
  The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET(+/+)) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice.
  
  
  RESULTS
  eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET(+/+) mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-) , developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e.g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e.g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation.
  
  
  CONCLUSIONS
  eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism.
authors: Center for Cardiovascular Research/Institute of Pharmacology, Charité, Berlin, Germany.
authors: Nicolas
authors: N
authors: Vignon-Zellweger
authors: Katharina
authors: K
authors: Relle
authors: Elodie
authors: E
authors: Kienlen
authors: Markus
authors: M
authors: Alter
authors: Patrick
authors: P
authors: Seider
authors: Juliya
authors: J
authors: Sharkovska
authors: Susi
authors: S
authors: Heiden
authors: Philipp
authors: P
authors: Kalk
authors: Karima
authors: K
authors: Schwab
authors: Barbara
authors: B
authors: Albrecht-Küpper
authors: Franz
authors: F
authors: Theuring
authors: Johannes-Peter
authors: JP
authors: Stasch
authors: Berthold
authors: B
authors: Hocher
mesh_terms: D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D001835:Body Weight; D003971:Diastole; D019332:Endothelin-1 / Q000235:genetics / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000502:physiology*; D009929:Organ Size; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D019332:Endothelin-1; D020097:Natriuretic Peptide, Brain; D052250:Nitric Oxide Synthase Type III