TY  - JOUR
A1  - Vignon-Zellweger, Nicolas
A1  - Relle, Katharina
A1  - Kienlen, Elodie
A1  - Alter, Markus L.
A1  - Seider, Patrick
A1  - Sharkovska, Juliya
A1  - Heiden, Susi
A1  - Kalk, Philipp
A1  - Schwab, Karima
A1  - Albrecht-Kuepper, Barbara
A1  - Theuring, Franz
A1  - Stasch, Johannes-Peter
A1  - Hocher, Berthold
T1  - Endothelin-1 overexpression restores diastolic function in eNOS knockout mice
JF  - Journal of hypertension
N2  - 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.
KW  - cardiovascular diseases
KW  - endothelin
KW  - nitric oxide
Y1  - 2011
U6  - https://doi.org/10.1097/HJH.0b013e3283450770
SN  - 0263-6352
SN  - 1473-5598
VL  - 29
IS  - 5
SP  - 961
EP  - 970
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  -