Endothelin-1 overexpression restores diastolic function in eNOS knockout mice

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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.

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.
Original languageEnglish
Pages (from-to)961-970
JournalJournal of Hypertension
Volume29
Issue number5
DOIs
Publication statusPublished - May 2011

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