Key result
ET-1 transgenic overexpression rescued diastolic dysfunction in eNOS knockout mice by regulating proteins involved in oxidative stress, myocyte contractility, and energy metabolism.
Why the study?
Does ET-1 overexpression improve diastolic function in eNOS knockout mice?
Does ET-1 overexpression improve diastolic function in eNOS knockout mice?
In a mouse model of eNOS deficiency, transgenic overexpression of ET-1 unexpectedly rescues diastolic dysfunction by modulating oxidative stress, contractility, and energy metabolism pathways.
Should not change clinical practice in diastolic dysfunction; hypothesis-generating in eNOS models and requires validation.
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.
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Vignon‐Zellweger et al. (2011) studied Nitric oxide deficiency and diastolic dysfunction. ET-1 transgenic overexpression vs. eNOS(-/-) mice without ET-1 overexpression was evaluated on Left ventricular function and morphology (diastolic dysfunction). ET-1 transgenic overexpression rescued diastolic dysfunction in eNOS knockout mice by regulating proteins involved in oxidative stress, myocyte contractility, and energy metabolism.
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