Nicolas Vignon-Zellweger, Katharina Relle, Elodie Kienlen, Markus L. Alter, Patrick Seider, Juliya Sharkovska, Susi Heiden, Philipp Kalk, Karima Schwab, Barbara Albrecht-Kuepper, Franz Theuring, Johannes-Peter Stasch, Berthold Hocher
- 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.
Methods and 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 appropriateBackground 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.
Methods and 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.
Conclusion 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.…
MetadatenVerfasserangaben: | Nicolas Vignon-Zellweger, Katharina Relle, Elodie Kienlen, Markus L. Alter, Patrick Seider, Juliya Sharkovska, Susi Heiden, Philipp Kalk, Karima Schwab, Barbara Albrecht-Kuepper, Franz Theuring, Johannes-Peter Stasch, Berthold HocherORCiDGND |
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DOI: | https://doi.org/10.1097/HJH.0b013e3283450770 |
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ISSN: | 0263-6352 |
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ISSN: | 1473-5598 |
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Titel des übergeordneten Werks (Englisch): | Journal of hypertension |
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Verlag: | Lippincott Williams & Wilkins |
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Verlagsort: | Philadelphia |
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Publikationstyp: | Wissenschaftlicher Artikel |
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Sprache: | Englisch |
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Jahr der Erstveröffentlichung: | 2011 |
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Erscheinungsjahr: | 2011 |
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Datum der Freischaltung: | 26.03.2017 |
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Freies Schlagwort / Tag: | cardiovascular diseases; endothelin; nitric oxide |
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Band: | 29 |
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Ausgabe: | 5 |
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Seitenanzahl: | 10 |
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Erste Seite: | 961 |
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Letzte Seite: | 970 |
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Fördernde Institution: | Deutsche Forschungsgemeinschaft; European Commission
[MEST-CT-2005-020268] |
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Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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Peer Review: | Referiert |
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