Details

Autor(en) / Beteiligte

• Vignon-Zellweger, Nicolas
• Relle, Katharina
• Kienlen, Elodie
• Alter, Markus
• Seider, Patrick
• Sharkovska, Juliya
• Heiden, Susi
• Kalk, Philipp
• Schwab, Karima
• Albrecht-Küpper, Barbara
• Theuring, Franz
• Stasch, Johannes-Peter
• Hocher, Berthold

Titel

Endothelin-1 overexpression restores diastolic function in eNOS knockout mice

Ist Teil von

• Journal of hypertension, 2011-05, Vol.29 (5), p.961-970

Ort / Verlag

Hagerstown, MD: Lippincott Williams & Wilkins, Inc

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• BACKGROUNDThe 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 ETeNOS mice. METHODS AND RESULTSeNOS and ETeNOS mice developed high blood pressure compared with wild-type and ET mice. Left ventricular catheterization showed that eNOS mice, but not ETeNOS, 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 ETeNOS 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 ETeNOS mice, eNOS mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e.g., cofilin-1 and cofilin-2). In ETeNOS mice, glycolysis was favored at the expense of fatty acid oxidation. CONCLUSIONeNOS 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.