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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-60182

Stein, S. SIRT1 diminishes atherogenesis by suppressing NF-kB signaling-mediated pro-inflammatory events. 2011, University of Zurich, Faculty of Science.

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Abstract

The aim of this PhD thesis was to investigate of the role of SIRT1 and Peroxisome
proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) in atherosclerosis.
Atherosclerosis is a chronic inflammatory disease resulting from the interaction of the vessel
wall with macrophages, T cells and oxidized low-density lipoproteins (oxLDL). Rupture of an
atherosclerotic plaque may result in thrombus formation and complete vessel occlusion, the
primary cause of myocardial infarction and stroke. SIRT1 and PGC-1α are enzymes with
important functions in various metabolic and anti-inflammatory processes. SIRT1 is a class
III histone deacetylase that mediates the effects of caloric restriction on lifespan and
metabolic pathways in various organisms. PGC-1α is a transcription coactivator involved in
mitochondrial biogenesis and metabolic processes; it is a target protein of SIRT1.
To study the role of these molecules in atherosclerosis, we crossed SIRT1+/- or PGC-1α-/- with
atherosclerosis-prone ApoE-/- mice, and compared ApoE-/- SIRT1+/+ with ApoE-/- SIRT1+/- mice
as well as ApoE-/- PGC-1α+/+ with ApoE-/- PGC-1α-/- mice, respectively.
We found that haploinsufficient ApoE-/- SIRT1+/- mice developed more atherosclerotic lesions
than ApoE-/- SIRT1+/+ mice. Using in vitro, ex vivo and in vivo approaches, we showed that
the atheroprotective effects of SIRT1 are mediated via suppression of NF-κB signaling:
SIRT1 prevents the expression of endothelial adhesion molecules and reduces the expression
of the scavenger receptor Lox-1 as well as macrophage foam cell formation. We further
demonstrated that suppression of NF-κB signaling diminishes the expression of tissue factor
(coagulation factor III) in human aortic endothelial cells.
ApoE-/- PGC-1α+/+ and ApoE-/- PGC-1α-/- mice did not differ in the amount of their
atherosclerotic lesions. ApoE-/- PGC-1α-/- mice had markedly reduced body and epididymal
white adipose tissue (WAT) weight, less plasma triglycerides, and differential expression of
various pro and anti-atherogenic factors. A balance of these anti- and pro-atherogenic factors
may explain the unchanged atherosclerotic phenotype of ApoE-/- PGC-1α-/- mice.
Taken together, our data reveal that the role of PGC-1α in atherogenesis remains to be
clarified. On the other hand, SIRT1 has both anti-atherogenic and anti-thrombotic functions.
Our findings suggest that SIRT1 activation may be a promising therapeutic approach to
impede atherosclerosis.

Item Type:Dissertation
Referees:Becher B, Matter C M, Donath M Y, Wahli W
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:25 Feb 2012 21:28
Last Modified:11 Sep 2012 18:56
Number of Pages:124
Related URLs:http://opac.nebis.ch/F/?local_base=NEBIS&CON_LNG=GER&func=find-b&find_code=SYS&request=006438603

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