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.