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Open Access 01-05-2016 | Original Contribution

Mild endothelial dysfunction in Sirt3 knockout mice fed a high-cholesterol diet: protective role of a novel C/EBP-β-dependent feedback regulation of SOD2

Authors: Stephan Winnik, Daniel S. Gaul, Giovanni Siciliani, Christine Lohmann, Lisa Pasterk, Natacha Calatayud, Julien Weber, Urs Eriksson, Johan Auwerx, Lambertus J. van Tits, Thomas F. Lüscher, Christian M. Matter

Published in: Basic Research in Cardiology | Issue 3/2016

Abstract

Sirtuin 3 (Sirt3) is an NAD⁺-dependent mitochondrial deacetylase associated with superoxide dismutase 2 (SOD2)-mediated protection from oxidative stress. We have reported accelerated weight gain and impaired metabolic flexibility in atherosclerotic Sirt3 ^−/− mice. Oxidative stress is a hallmark of endothelial dysfunction. Yet, the role of Sirt3 in this context remains unknown. Thus, we aimed to unravel the effects of endogenous Sirt3 on endothelial function and oxidative stress. Knockdown of Sirt3 in human aortic endothelial cells (HAEC) increased intracellular mitochondrial superoxide accumulation, as assessed by electron spin resonance spectroscopy and fluorescence imaging. Endothelium-dependent relaxation of aortic rings from Sirt3 ^−/− mice exposed to a normal diet did not differ from wild-type controls. However, following 12 weeks of high-cholesterol diet and increasing oxidative stress, endothelial function of Sirt3 ^−/− mice was mildly impaired compared with wild-type controls. Relaxation was restored upon enhanced superoxide scavenging using pegylated superoxide dismutase. Knockdown of Sirt3 in cultured HAEC diminished SOD2 specific activity, which was compensated for by a CCAAT/enhancer binding protein beta (C/EBP-β)-dependent transcriptional induction of SOD2. Abrogation of this feedback regulation by simultaneous knockdown of C/EBP-β and Sirt3 exacerbated mitochondrial superoxide accumulation and culminated into endothelial cell death upon prolonged culture. Taken together, Sirt3 deficiency induces a mild, superoxide-dependent endothelial dysfunction in mice fed a high-cholesterol diet. In cultured endothelial cells, a novel C/EBP-β-dependent rescue mechanism maintains net SOD2 activity upon transient knockdown of Sirt3.

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Title: Mild endothelial dysfunction in Sirt3 knockout mice fed a high-cholesterol diet: protective role of a novel C/EBP-β-dependent feedback regulation of SOD2
Authors: Stephan Winnik
Daniel S. Gaul
Giovanni Siciliani
Christine Lohmann
Lisa Pasterk
Natacha Calatayud
Julien Weber
Urs Eriksson
Johan Auwerx
Lambertus J. van Tits
Thomas F. Lüscher
Christian M. Matter
Publication date: 01-05-2016
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 3/2016
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-016-0552-7

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Mild endothelial dysfunction in Sirt3 knockout mice fed a high-cholesterol diet: protective role of a novel C/EBP-β-dependent feedback regulation of SOD2

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