Jahresbericht der Klinik - Klinik für Kardiologie - UniversitätsSpital ...

Christian M. Matter, MD
Research Group Leader
Basic Cardiovascular Research
Atherothrombosis and SIRT1 –
from mice to men
SIRT1 – from experimental atherothrombosis to
clinical application
Obesity, type 2 diabetes and dyslipidemia are important risk factors
for atherosclerosis with which they share central inflammatory
pathways. Christian Matter’s group has applied genetic modulation
of relevant pathways in mice (JNK2 and PARP1) that allows to get
mechanistic insight into these diseases. Sirtuins are deacetylases that
mediate the effects of caloric restriction on lifespan and metabolic
pathways. Recently, they have shown that the deacetylase SIRT1 confers
protective effects on atherothrombosis by diminishing foam cell
formation, endothelial activation, and tissue factor activity. Supported
by the Swiss National Science Foundation and the Zurich Center
for Integrative Human Physiology (ZIHP) they are now translating this
concept to the clinical context [Fig. 1]:
Along these lines, they have investigated
1. SIRT1 levels in inflammatory cells, thrombi and plaques of patients
with acute coronary syndromes (ACS) – as part of a Swiss-wide
cooperation within the SNF-SPUM program with Bern, Geneva,
Lausanne.
2. patients with a SIRT1 mutation – cooperation lead by Marc
Donath (Basel) and David Sinclair (Boston).
3. effects of pharmacological SIRT1 activation on atherosclerosis
and lipid metabolism – cooperation with Thomas Lutz (Zurich),
Johan Auwerx and Kristina Schoonjans (Lausanne), Bart Staels
(Lille, FR), and Sirtris (Cambridge, USA).
The initial experiments were performed by Sokrates Stein, Melroy
Miranda, Stephan Winnik and Tine Lohmann; in vivo thrombosis
assays were performed with Felix Tanner’s group by Susanna Sluka.
They anticipate that these exciting research avenues help them to
identify novel therapeutic targets and indications of SIRT1 activation
in atherothrombosis and associated risk factors.
Relevance of other sirtuins and fibroblast activation
protein (FAP) in atherothrombosis
Using similar approaches complemented by in vitro and in vivo
thrombosis assays, Christian Matter’s group is investigating the role
of other sirtuins and matrix-associated proteins: Other members of
the sirtuin family are elucidated by Dr. Stephan Winnik (cooperations
with Johan Auwerx and Bernard Thorens in Lausanne), the role of
fibroblast activation protein (FAP) by Dr. Chad Brokopp (cooperations
with Simon Hoerstrup, Zurich and Mark Gorrell, Syndney, AU) and
of Cyr61 by Dr. Roland Klingenberg (cooperation with Arnold von
Eckardstein).
SIRT1
activation
Fig. 1 Investigating novel targets of SIRT1 in atherothrombosis in
mice and human cells using genetic and / or pharmacological SIRT1
modulation help to translate this concept to the clinical arena.
Fig. 2 Christian Matter (MD) and his team (left to right): Melroy
Miranda (PhD student), Christian Matter (MD), Christine Lohmann
(technician) and Stephan Winnik (MD)